CN109563043A - The substituted pyridine of inhibitor as DNMT1 - Google Patents

The substituted pyridine of inhibitor as DNMT1 Download PDF

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Publication number
CN109563043A
CN109563043A CN201780036908.XA CN201780036908A CN109563043A CN 109563043 A CN109563043 A CN 109563043A CN 201780036908 A CN201780036908 A CN 201780036908A CN 109563043 A CN109563043 A CN 109563043A
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base
dicyano
sulfenyl
amino
phenyl
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CN109563043B (en
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N.D.亚当斯
A.B.贝诺维茨
M.L.鲁埃达贝内德
K.A.埃文斯
D.T.福斯贝纳
B.W.金
M.李
J.I.吕戈
W.H.米勒
A.J.赖夫
S.P.罗默里尔
S.J.施密特
R.J.巴特林
K.M.戈德伯格
A.M.乔丹
C.S.克肖
A.劳夫
B.瓦兹科维茨
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Cancer Research Technology Ltd
GlaxoSmithKline Intellectual Property Development Ltd
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Cancer Research Technology Ltd
GlaxoSmithKline Intellectual Property Development Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The present invention relates to substituted pyridine derivates.In particular it relates to the compound of formula (Iar): wherein Yar、X1ar、X2ar、R1ar、R2ar、R3ar、R4arAnd R5arAs defined herein；Or its pharmaceutically acceptable salt or prodrug.The compound of the present invention is the selective depressant of DNMT1 and can be used for syndrome, β hemoglobinopathy, drepanocytosis, sickle-cell anemia and beta Thalassemia before treating cancer, cancer, and inhibits related disease with DNMT1.Therefore, the invention further relates to the pharmaceutical compositions comprising the compounds of this invention.The invention further relates to use the compounds of this invention or pharmaceutical composition comprising the compounds of this invention is come the method that inhibits DNMT1 activity and treat relative illness.

Description

The substituted pyridine of inhibitor as DNMT1
Technical field
The present invention relates to substituted pyridine derivates, are dnmt rna 1 (DNMT1) active selective depression Agent.The invention further relates to the pharmaceutical composition comprising the compound and using the compound before treating cancer, cancer syndrome, β hemoglobinopathy, drepanocytosis, sickle cell anemia and beta Thalassemia and other inhibit in related disease with DNMT1 Method.
Background technique
Epigenetics is a kind of method that the DNA sequence dna independently of basis opens and closes gene.In gene promoter The DNA methylation of generation is an example of inhibition epigenetic label, leads to chromatin densification and gene silencing. DNA methylation is mediated by dnmt rna (DNMT) protein family, which is made of four family members.Three Family member DNMT1, DNMT3A and DNMT3B contain dnmt rna activity.These three members are responsible for establishing from the beginning DNA first Base mode, and DNMT1 is mainly responsible for the methylation patterns after maintaining DNA replication dna in subchain.
In cancer, DNA methylation mode becomes abnormal, leads to whole hypomethylation and part height in promoter region Methylation.This can lead to downstream silencing (Ting et al. Genes Dev.2006 of tumor suppressor gene；20:3215-3231).Separately Outside, the silencing of DNMT1 leads expressing again for deoxyribonucleic acid (DNA) demethylation and tumor suppressor gene, leads to Tumor growth inhibition (Zhou etc. People, Oncol.Lett.2014；5:2130-2134).
DNA methylation inhibitor (referred to as DNA low hypomethylation agent) is clinical verification for treating MDS, AML and CMML Anti-cancer therapies.Although these medicaments are available, toxicity, entity tumor practicability and oral administration biaavailability in terms of still Be significantly improved chance.Therefore, new DNMT inhibitor is for treating cancer and/or any disease mediated by DNA methylation Disease or illness are all meaningful.The present invention it is particularly interesting that selectively targeted DNMT1 with prevent will be different during duplication Normal methylation patterns (such as those of generation in cancer) are broadcast to subchain.
US 2008/0132525 and WO 2006/078752 describe the inhibitor of dnmt rna.CA 2030875 Describe the method and probe for detecting nucleoside transporter and the method for generating probe.
Hemoglobinopathy
Hemoglobin disorder, such as sickle-cell anemia and β-thalassemia are the most common heredity in the world Blood disease.Sickle-cell anemia and beta Thalassemia are characterized in that hemoglobin obstacle, hemoglobin are in red blood cell Oxygen carrying albumen composition.In structure, hemoglobin is usually made of two pairs of protein and four haemachrome molecules.Adult and About four months or more children express a kind of hemoglobin form for being known as adult gemoglobin, mainly by two α-pearl egg White composition is matched with two beta-globins and four haemachrome molecules.However, usually mainly expression fetus is blood red by fetus and baby Albumen is composed of by two α-globins and two γ-globins and four haemachrome molecules.Note that there are two types of forms γ-globin, referred to as G- γ and A- γ, they are encoded by two different genes (HBG1 and HBG2), but functionally quite In largely；Fetal hemoglobin refers to that a pair of of G- γ and/or A- γ adds a pair of of α-globin plus four ferrohemes point Any combination of son.
In herrik syndrome, the gene for encoding beta-globin contains the mutation for leading to abnormal hemoglobin structure, And make red blood cell using characteristic falciform shape under certain conditions.This reaping hook shape causes red blood cell plasticity to drop Low, capillary haulage time extends, and frequent vascular occlusion process, these processes meeting injury tissue simultaneously causes patient to send out Disease.On the contrary, β-thalassemia is characterized in that beta-globin generation is not enough in conjunction with the α-globin normally generated.Thus The alpha globin accumulation of generation is toxic to erythroid precursors, and leads to invalid RBC acceptor garland rate and extensive erythrocyte hemolysis.
It there is no the drug therapy of approval at present to cure sickle-cell anemia or β-thalassemia.However, it has proven convenient that It generates the increase of the erythrocyte number of fetal hemoglobin and the overall of fetal hemoglobin level in each red blood cell is combined to increase Add is provided in herrik syndrome and sickle cell patient by reducing the frequency of Acute vessel closure critical days Clinical benefit.Although β-thalassemia disease biological shows fetus is blood red in addition, not confirming by clinical It is also likely to be the possible strategy for treating this disease that albumen generation, which increases to high level,.
The purpose of the treatment method, the i.e. HBG1 and HBG2 gene of silencing are disinthibited, and can pass through that intervene red blood cell raw Epigenetic process in targets.The change of DNA methylation is the key that decision event in hematopoiesis, and indicating causes The differentiation milestone of various cell lineage sizings.During RBC acceptor garland rate, the quick reduction of whole DNA methylation is shown pair The sizing point (commitment point) of red blood cell specificity regulatory factor GATA1 and KLF1 expression, and it is thin to hematopoiesis ancestral The inhibition (1,2) of born of the same parents' regulatory factor GATA2 and PU.1.For the erythroid progenitor cells in Adult Human Bone Marrow, beta-globin HBB gene DNA in promoter region becomes not methylating, the high level expression corresponding to beta-globin.On the contrary, HBG1 and HBG2 gene The promoter high methylation of seat, causes the expression of gamma globulin to greatly reduce (3).Although dnmt rna DNMT1, It is expressed in each comfortable erythroid progenitor cells of DNMT3A and DNMT3B, but the expression of DNMT1 is relatively high, especially in erythroid differentiation Final stage show it globin gene adjusting in play a leading role (2).5-azacitidine and 5- azepine -2'- deoxidation born of the same parents Glycosides (Decitabine) is general DNMT inhibitor, is known fetal hemoglobin inducer in erythroid progenitor cells.In red blood cell In like cell culture medium and the In vivo model of fetal hemoglobin induction (4,5), being handled with these reagents causes in HBG promoter The methylation in the site CpG reduces, while γ globin protein expression is increase accordingly.In addition, in one group of limited clinical research In, two kinds of drugs cause sickle cell anemia, drepanocytosis and β-patients with thalassemia fetal hemoglobin to increase (6-9).Although effectively inducing fetal hemoglobin, due to worrying long-term safety, dose-limiting toxicity and unsuitable Administration route, these drugs are not yet widely used in treatment sickle-cell anemia, drepanocytosis or β-thalassemia.
Bibliography
(1)Pop R,Shearstone JR,Shen Q,Liu Y,Hallstrom K,Koulnis M,et al.A key commitment step in erythropoiesis is synchronized with the cell cycle clock through mutual inhibition between PU.1and S-phase progression.2010；8.
(2)Shearstone JR,Pop R,Bock C,Boyle P,Meissner A,Socolovsky M.Global DNA demethylation during mouse erythropoiesis in vivo.2011；334:799-802.
(3)Mabaera R,Richardson CA,Johnson K,Hsu M,Fiering S,Lowrey CH.Developmental-and differentiation-specific patterns of humanand globin promoter DNA methylation.2007；110:1343-52.
(4)Chin J,Singh M,Banzon V,Vaitkus K,Ibanez V,Kouznetsova T,et al.Transcriptional activation of theglobin gene in baboons treated withdecitabine and in cultured erythroid progenitor cells involves differentmechanisms.2009；37:1131-42.
(5)Akpan I,Banzon V,Ibanez V,Vaitkus K,DeSimone J,Lavelle D.Decitabine increases fetal hemoglobin in Papio anubis by increasing globin gene transcription.2010；38:989-93.
(6)Dover GJ,Charache SH,Boyer SH,Talbot J,Smith KD.5-Azacytidine increases fetal hemoglobin production in a patient with sickle cell disease.1983；134:475-88.
(7)Saunthararajah Y,Hillery CA,Lavelle D,Molokie R,Dorn L,Bressler L, et al.Effects of 5-aza--deoxycytidine on fetal hemoglobin levels,red cell adhesion,and hematopoietic differentiation in patients with sickle cell disease.2003；102:3865-70.
(8)Ley TJ,DeSimone J,Noguchi CT,Turner PH,Schechter AN,Heller P,et al.5-Azacytidine increasesglobin synthesis and reduces the proportion of dense cells in patients with sickle cell anemia.1983；62:370-80.
(9)Lowrey CH,Nienhuis AW.Brief report:Treatment with azacitidine of patients with end-stagethalassemia.1993；329:845-8.
It is an object of the present invention to provide the noval chemical compounds of the selective depressant as DNMT1.
It is a further object to provide the compounds for increasing the generation of γ globin, to also increase people's erythroid cells The generation of middle fetal hemoglobin.Therefore, the compounds of this invention can be used for treating sickle-cell anemia and drepanocytosis.With The treatment of these compounds can also improve β-thalassemia.
It is a further object of the present invention to provide pharmaceutical compositions, and it includes drug excipients and formula (I) compound.
It is a further object of the present invention to provide syndrome before treating cancer, cancer, β hemoglobinopathy, such as drepanocytosis, The method of sickle cell anemia and beta Thalassemia comprising the administration active new selective depressant of DNMT1.
Summary of the invention
The present invention relates to substituted pyridine derivates.In particular it relates to the compound of formula (Iar):
Wherein Yar, X1ar, X2ar, R1ar, R2ar, R3ar, R4ar and R5ar as defined below；Or it can pharmaceutically connect The salt or prodrug received.
The invention further relates to following discoveries: formula (I) compound is active and right as the inhibitor of DNMT1 DNMT3A and DNMT3B has selectivity.
The invention further relates to the methods for the treatment of cancer comprising a effective amount of formula (I) is administered to subject with this need DNMT1 inhibitory compound；Or its pharmaceutically acceptable salt.
The invention further relates to the methods of syndrome before treatment cancer comprising is administered to subject with this need a effective amount of The DNMT1 inhibitory compound of formula (I)；Or its pharmaceutically acceptable salt.
The invention further relates to the methods for the treatment of β hemoglobinopathy comprising effective quantity is administered to subject with this need Formula (I) DNMT1 inhibitory compound；Or its pharmaceutically acceptable salt.
The invention further relates to the methods for the treatment of drepanocytosis comprising is administered to subject with this need a effective amount of The DNMT1 inhibitory compound of formula (I)；Or its pharmaceutically acceptable salt.
The invention further relates to the methods for the treatment of sickle-cell anemia comprising effective to subject with this need administration The DNMT1 inhibitory compound of the formula (I) of amount；Or its pharmaceutically acceptable salt.
The invention further relates to the methods for the treatment of beta Thalassemia comprising effective quantity is administered to subject with this need Formula (I) DNMT1 inhibitory compound；Or its pharmaceutically acceptable salt.
The invention further relates to formula (I) compound or its pharmaceutically acceptable salts, are used to treat.
The invention further relates to formula (I) compound or its pharmaceutically acceptable salts, are used for treating cancer.
The invention further relates to formula (I) compound or its pharmaceutically acceptable salts, are used to treat syndrome before cancer.
The invention further relates to formula (I) compound or its pharmaceutically acceptable salts, are used to treat β hemoglobinopathy.
The invention further relates to formula (I) compound or its pharmaceutically acceptable salts, are used to treat drepanocytosis.
The invention further relates to formula (I) compound or its pharmaceutically acceptable salts, are used to treat sickle-cell anemia.
The invention further relates to formula (I) compound or its pharmaceutically acceptable salts, are used to treat beta Thalassemia.
The invention further relates to formula (I) compound or its pharmaceutically acceptable salts in the preparation of medicament for cancer treatment Purposes.
The invention further relates to formula (I) compound or its pharmaceutically acceptable salts to prepare for treating syndrome before cancer Purposes in drug.
The invention further relates to formula (I) compound or its pharmaceutically acceptable salt in preparation for treating β hemoglobinopathy Drug in purposes.
The invention further relates to formula (I) compound or its pharmaceutically acceptable salt in preparation for treating drepanocytosis Purposes in drug.
It is poor for treating Sickle in preparation that the invention further relates to formula (I) compounds or its pharmaceutically acceptable salt Purposes in the drug of blood.
The invention further relates to formula (I) compound or its pharmaceutically acceptable salt in preparation for treating beta Thalassemia Drug in purposes.
By the invention is pharmaceutical composition, and it includes pharmaceutical carrier and formula (I) compound or its is pharmaceutically acceptable Salt.
The invention further relates to pharmaceutical composition as defined above, it is used to treat.
The invention also includes be to be total to DNMT1 inhibitory compound of the invention and other one or more antitumor agents With the method for administration.
The invention also includes be that DNMT1 inhibitory compound of the invention and one or more other fetuses is blood red The method of protein induced dose of co-administered.
The invention also includes be by DNMT1 inhibitory compound of the invention and one or more other to mitigate β blood The method of the drug co-administered of the seriousness of Lactoferrin disease.
The invention also includes be by DNMT1 inhibitory compound of the invention and one or more other to mitigate falciforms The method of the drug co-administered of the seriousness of cellulous anemia.
The invention also includes be by DNMT1 inhibitory compound of the invention and one or more other to mitigate falciforms The method of the drug co-administered of the seriousness of cytopathy.
The invention also includes be by DNMT1 inhibitory compound of the invention and it is one or more it is other with mitigating β The method of the drug co-administered of the seriousness of middle sea anaemia.
The invention further relates to the combinations for treatment comprising (i) formula (I) compound of therapeutically effective amount or its pharmaceutically Acceptable salt；(ii) at least one antitumor agent.
The invention further relates to the combinations for treatment comprising (i) formula (I) compound of therapeutically effective amount or its pharmaceutically Acceptable salt；(ii) at least one other fetal hemoglobin inducers.
The invention further relates to the combinations for treatment comprising (i) formula (I) compound of therapeutically effective amount or its pharmaceutically Acceptable salt；The drug of (ii) at least one other seriousness for mitigating β hemoglobinopathy.
The invention further relates to the combinations for treatment comprising (i) formula (I) compound of therapeutically effective amount or its pharmaceutically Acceptable salt；The drug of (ii) at least one other seriousness for mitigating sickle-cell anemia.
The invention further relates to the combinations for treatment comprising (i) formula (I) compound of therapeutically effective amount or its pharmaceutically Acceptable salt；The drug of (ii) at least one other seriousness for mitigating drepanocytosis.
The invention further relates to the combinations for treatment comprising (i) formula (I) compound of therapeutically effective amount or its pharmaceutically Acceptable salt；The drug of (ii) at least one other seriousness for mitigating beta Thalassemia.
Attached drawing description
Figure 1A describes influence of the compound A to erythroid progenitor cells (EPC).With compound A to fetal hemoglobin (HbF) ELISA (empty circles) and cell growth measurement (solid circles) treat 5 days representative results (every group of n=3 research).
Figure 1B depicts the influence that compound A methylates to HBG1 and HBG2DNA.Erythroid progenitor cells (EPC) uses medium It (grey bar) or is handled 3 days with 5 μM of compound A (black bar), extracts genomic DNA, and in the promoter region of HBG1 and HBG2 Bisulfite sequencing is carried out to 9 locus in domain, is described as the site of DNMT1 cytosine methylation before them.First Base site-tag is the position relative to each initiation site.
Fig. 2A depicts influence of the compound A to fetal hemoglobin in transgene mouse model.By compound A with 10 or 50mg/kg is oral to give drepanocytosis (SCD) model transgenic mice, and daily BID causes %HbF egg by HPLC measurement White dose dependent increases.
Fig. 2 B depicts influence of the compound A to fetal hemoglobin in transgene mouse model.By compound A with 10 or 50mg/kg is oral to give SCD transgenic mice, and daily BID causes %F- desmacyte and %F- by flow cytometry measure The dose dependent of RBC increases.
Detailed description of the invention
The present invention relates to the purposes of formula (Iar) compound and formula (Iar) compound in the methods of the invention:
Wherein:
X1arAnd X2arIndependently selected from:
Hydrogen,
Cyano,
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
Re,
-OC1-6Alkyl,
-ORe,
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl,
By RdReplace 1-4 Heterocyclylalkyl,
- SH, and
-SRa；
YarIt is selected from: S, NH, NRz, O, S (O) and S (O)2；
R1arIt is selected from:
Amino,
-NHRa,
-NRbRc,
Cyano,
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
Re,
-OC1-6Alkyl,
-ORe,
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl,
By RdReplace 1-4 Heterocyclylalkyl,
Aryl,
By RdReplace 1-4 aryl,
Heteroaryl,
By RdReplace 1-4 heteroaryl,
- SH, and
-SRa；
R2arIt is selected from:
Hydrogen,
C1-6Alkyl,
Re,
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl,
By RdReplace 1-4 Heterocyclylalkyl,
-C(O)ORa,
-C(O)NHRa, and
-C(O)NRbRc；
R3arIt is selected from:
Hydrogen,
Aryl,
By RdReplace 1-4 aryl,
Heteroaryl, and
By RdReplace 1-4 heteroaryl；
R4arIt is selected from:
Hydrogen,
C1-6Alkyl,
Re,
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl,
By RdReplace 1-4 Heterocyclylalkyl,
-C(O)ORa,
-C(O)NHRa, and
-C(O)NRbRc；
R5arIt is selected from:
Amino,
-NHRa,
-NRbRc,
Aryl,
By RdReplace 1-4 aryl,
-OC1-6Alkyl,
-ORe,
- O aryl,
By RdReplace 1-4-O aryl,
- O heteroaryl,
By RdReplace 1-4-O heteroaryl,
- SH, and
-SRa；
Wherein:
Each RaIndependently selected from
C1-6Alkyl,
Re,
Aryl,
By RdReplace 1-4 aryl,
Heteroaryl,
By RdReplace 1-4 heteroaryl,
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl, and
By RdReplace 1-4 Heterocyclylalkyl；
RbAnd RcIndependently selected from:
C1-6Alkyl,
Re,
Aryl,
By RdReplace 1-4 aryl,
Heteroaryl,
By RdReplace 1-4 heteroaryl；
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl, and
By RdReplace 1-4 Heterocyclylalkyl, or
RbAnd RcNitrogen connected to them and optional 1-3 additional hetero atoms are formed together Heterocyclylalkyl, optionally Replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
Re,
Aryl,
By RdReplace 1-4 aryl,
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl, and
By RdReplace 1-4 Heterocyclylalkyl,
C1-4Alkoxy,
The C replaced by 1-6 substituent groups independently selected from the following1-4Alkoxy: fluorine, oxo ,-OH ,-COOH ,-NH2 With-CN,
- CN,
Oxo,
- OH,
- COOH,
-NO2,
-NH2,
-N(H)C1-4Alkyl,
-N(H)Re,
-N(C1-4Alkyl)2,
-NReRe,
SO2NH2,
SO2CH2CH3, and
SO2CH3；
Each RdIndependently selected from:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
Re,
Heteroaryl,
By RxReplace 1-4 heteroaryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Naphthenic base,
By RxReplace 1-4 naphthenic base,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Heterocyclylalkyl,
By RxReplace 1-4 Heterocyclylalkyl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Aryl,
By RxReplace 1-4 aryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
C1-4Alkoxy,
Replaced 1-4 C by fluorine1-4Alkoxy,
- O aryl,
By RxReplace 1-4-O aryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- C (O) H,
-C(O)Rzz,
- C (O) aryl,
By RzzReplace 1-4 times-C (O) aryl,
- C (O) heteroaryl,
By RzzReplace 1-4 times-C (O) heteroaryl,
- OC (O) H,
-CO(O)Rzz,
- OC (O) aryl,
By RzzReplace 1-4 times-CO (O) aryl,
- OC (O) heteroaryl,
By RzzReplace 1-4 times-OC (O) heteroaryl,
Sulfydryl,
-SRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- S (O) H,
-S(O)Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2H,
-S(O)2Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2NH2,
-S(O)2NHRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl, and by 1-6 The C that a substituent group independently selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-NHS(O)2H,
-NHS(O)2Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- NHC (O) H,
-NHC(O)Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-C(O)NH2,
-C(O)NHRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-C(O)NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl, and by 1-6 The C that a substituent group independently selected from the following replaces1-6Alkyl: fluorine, oxo,
-OH、-COOH、-NH2With-CN,
- C (O) OH,
-C(O)ORx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Oxo,
Hydroxyl,
Amino,
-NHRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl, and by 1-6 The C that a substituent group independently selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Nitro,
Cyano,
-NHC(O)NH2,
-NHC(O)NHRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-NHC(O)NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl, and by 1-6 The C that a substituent group independently selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Each ReIndependently selected from:
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
-OC1-6Alkyl,
- the OC replaced by 1-6 substituent groups independently selected from the following1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2 With-CN, sulfydryl,
-SRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- S (O) H,
-S(O)Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2H,
-S(O)2Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Oxo,
Hydroxyl,
Amino,
-NHRxx,
Wherein RxxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-ORxy、-COOH、-CN、-OC1-5Alkyl, by fluorine and-NRxyRxzReplace 1-6 times - OC1-5Alkyl, wherein RxyAnd RxzIndependently selected from: hydrogen, aryl, C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
-NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 The C that substituent group independently selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Guanidine radicals,
- C (O) OH,
-C(O)ORx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-C(O)NH2,
-C(O)NHRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-C(O)NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 The C that substituent group independently selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Aryl,
By RxReplace 1-4 aryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- O aryl,
By RxReplace 1-4-O aryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Heteroaryl,
By RxReplace 1-4 heteroaryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- O heteroaryl,
By RxReplace 1-4-O heteroaryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Naphthenic base,
By RxReplace 1-4 naphthenic base,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Heterocyclylalkyl,
By RxReplace 1-4 Heterocyclylalkyl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-4 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2NH2,
-S(O)2NHRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2NRx1Rx2,
Wherein each Rx1And Rx2It is independent to be selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 solely The on the spot C that substituent group selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN ,-NHS (O)2H,
-NHS(O)2Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-NHC(O)NHRxp,
Wherein RxpReplaced selected from heteroaryl, naphthenic base, Heterocyclylalkyl and by 1-4 substituent groups independently selected from the following C1-6Alkyl :-COOH ,-NH2With-CN,
-NHC(O)NRx3Rx4,
Wherein Rx3And Rx4Be each independently selected from heteroaryl, naphthenic base, Heterocyclylalkyl and by 1-6 independently selected from Under substituent group replace C1-6Alkyl :-COOH ,-NH2With-CN,
Nitro and
Cyano；
Each RfIt independently is optionally by ReReplace 1-6 C1-6Alkyl；
Each RgIt independently is optionally by RxReplace 1-5 aryl,
Wherein RxIndependently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6It alkyl and is independently selected by 1-6 The C replaced from substituent group below1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Each RhIt independently is optionally by RxReplace 1-5 heteroaryl,
Wherein RxIndependently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6It alkyl and is independently selected by 1-6 The C replaced from substituent group below1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN, and
RzIt is selected from
C1-6Alkyl,
Re,
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl, and
By RdReplace 1-4 Heterocyclylalkyl；
RzzIt is selected from
C1-6Alkyl, and
Re；
On condition that:
R2ar、R3arAnd R4arAt least one be hydrogen,
R2ar、R3arAnd R4arNot all for hydrogen and
X1arAnd X2arIt is not all hydrogen；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, in formula (Iar) compound, R2arFor-C (O) NH2。
Suitably, in formula (Iar) compound, R3arFor optionally by RdReplace 1-4 aryl.
Included in the compounds of this invention and it is used in the method for the present invention be formula (I) compound:
Wherein:
X1And X2Independently selected from:
Hydrogen,
Cyano,
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
Re,
-OC1-6Alkyl,
-ORe,
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl,
By RdReplace 1-4 Heterocyclylalkyl,
- SH, and
-SRa；
Y is selected from: S, NH, NRz, O, S (O) and S (O)2；
R1It is selected from:
Amino,
-NHRa,
-NRbRc,
Cyano,
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
Re,
-OC1-6Alkyl,
-ORe,
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl,
By RdReplace 1-4 Heterocyclylalkyl,
- SH, and
-SRa；
R2It is selected from:
Hydrogen,
C1-6Alkyl,
Re,
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl,
By RdReplace 1-4 Heterocyclylalkyl,
-C(O)ORa,
-C(O)NHRa, and
-C(O)NRbRc；
R3It is selected from:
Hydrogen,
Aryl,
By RdReplace 1-4 aryl,
Heteroaryl, and
By RdReplace 1-4 heteroaryl；
R4It is selected from:
Hydrogen,
C1-6Alkyl,
Re,
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl,
By RdReplace 1-4 Heterocyclylalkyl,
-C(O)ORa,
-C(O)NHRa, and
-C(O)NRbRc；
R5It is selected from:
Amino,
-NHRa,
-NRbRc,
Aryl,
By RdReplace 1-4 aryl,
-OC1-6Alkyl,
-ORe,
- O aryl,
By RdReplace 1-4-O aryl,
- O heteroaryl,
By RdReplace 1-4-O heteroaryl,
- SH, and
-SRa；
Wherein:
Each RaIndependently selected from
C1-6Alkyl,
Re,
Aryl,
By RdReplace 1-4 aryl,
Heteroaryl,
By RdReplace 1-4 heteroaryl,
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl, and
By RdReplace 1-4 Heterocyclylalkyl；
RbAnd RcIndependently selected from:
C1-6Alkyl,
Re,
Aryl,
By RdReplace 1-4 aryl,
Heteroaryl,
By RdReplace 1-4 heteroaryl；
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl, and
By RdReplace 1-4 Heterocyclylalkyl, or
RbAnd RcNitrogen connected to them and optional 1-3 additional hetero atoms are formed together Heterocyclylalkyl, optionally Replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
Re,
Aryl,
By RdReplace 1-4 aryl,
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl, and
By RdReplace 1-4 Heterocyclylalkyl,
C1-4Alkoxy,
The C replaced by 1-6 substituent groups independently selected from the following1-4Alkoxy: fluorine, oxo ,-OH ,-COOH ,-NH2 With-CN,
- CN,
Oxo,
- OH,
- COOH,
-NO2,
-NH2,
-N(H)C1-4Alkyl,
-N(H)Re,
-N(C1-4Alkyl)2,
-NReRe,
SO2NH2,
SO2CH2CH3, and
SO2CH3；
Each RdIndependently selected from:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
Re,
Heteroaryl,
By RxReplace 1-4 heteroaryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Naphthenic base,
By RxReplace 1-4 naphthenic base,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Heterocyclylalkyl,
By RxReplace 1-4 Heterocyclylalkyl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Aryl,
By RxReplace 1-4 aryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
C1-4Alkoxy,
Replaced 1-4 C by fluorine1-4Alkoxy,
- O aryl,
By RxReplace 1-4-O aryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- C (O) H,
-C(O)Rzz,
- C (O) aryl,
By RzzReplace 1-4 times-C (O) aryl,
- C (O) heteroaryl,
By RzzReplace 1-4 times-C (O) heteroaryl,
- OC (O) H,
-CO(O)Rzz,
- OC (O) aryl,
By RzzReplace 1-4 times-CO (O) aryl,
- OC (O) heteroaryl,
By RzzReplace 1-4 times-OC (O) heteroaryl,
Sulfydryl,
-SRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- S (O) H,
-S(O)Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2H,
-S(O)2Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2NH2,
-S(O)2NHRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl, and by 1-6 The C that a substituent group independently selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-NHS(O)2H,
-NHS(O)2Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- NHC (O) H,
-NHC(O)Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-C(O)NH2,
-C(O)NHRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-C(O)NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl, and by 1-6 The C that a substituent group independently selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- C (O) OH,
-C(O)ORx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Oxo,
Hydroxyl,
Amino,
-NHRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl, and by 1-6 The C that a substituent group independently selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Nitro,
Cyano,
-NHC(O)NH2,
-NHC(O)NHRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-NHC(O)NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl, and by 1-6 The C that a substituent group independently selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Each ReIndependently selected from:
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
-OC1-6Alkyl,
- the OC replaced by 1-6 substituent groups independently selected from the following1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2 With-CN, sulfydryl,
-SRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- S (O) H,
-S(O)Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2H,
-S(O)2Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Oxo,
Hydroxyl,
Amino,
-NHRxx,
Wherein RxxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-ORxy、-COOH、-CN、-OC1-5Alkyl, by fluorine and-NRxyRxzReplace 1-6 times - OC1-5Alkyl, wherein RxyAnd RxzIndependently selected from: hydrogen, aryl, C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
-NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 The C that substituent group independently selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN, guanidine radicals,
- C (O) OH,
-C(O)ORx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-C(O)NH2,
-C(O)NHRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-C(O)NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 The C that substituent group independently selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN, aryl,
By RxReplace 1-4 aryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- O aryl,
By RxReplace 1-4-O aryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Heteroaryl,
By RxReplace 1-4 heteroaryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- O heteroaryl,
By RxReplace 1-4-O heteroaryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Naphthenic base,
By RxReplace 1-4 naphthenic base,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Heterocyclylalkyl,
By RxReplace 1-4 Heterocyclylalkyl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2NH2,
-S(O)2NHRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 The C that substituent group independently selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-NHS(O)2H,
-NHS(O)2Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-NHC(O)NHRxp,
Wherein RxpReplaced selected from heteroaryl, naphthenic base, Heterocyclylalkyl and by 1-4 substituent groups independently selected from the following C1-6Alkyl :-COOH ,-NH2With-CN,
-NHC(O)NRx3Rx4,
Wherein Rx3And Rx4Be each independently selected from heteroaryl, naphthenic base, Heterocyclylalkyl and by 1-6 independently selected from Under substituent group replace C1-6Alkyl :-COOH ,-NH2With-CN,
Nitro and
Cyano；
Each RfIt independently is optionally by ReReplace 1-6 C1-6Alkyl；
Each RgIt independently is optionally by RxReplace 1-5 aryl,
Wherein RxIndependently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6It alkyl and is independently selected by 1-6 The C replaced from substituent group below1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Each RhIt independently is optionally by RxReplace 1-5 heteroaryl,
Wherein RxIndependently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6It alkyl and is independently selected by 1-6 The C replaced from substituent group below1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN, and
RzIt is selected from
C1-6Alkyl,
Re,
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl, and
By RdReplace 1-4 Heterocyclylalkyl；
RzzIt is selected from
C1-6Alkyl, and
Re；
On condition that:
R2、R3And R4At least one of be hydrogen,
R2、R3And R4Not all for hydrogen and
X1And X2It is not all hydrogen；
Or its pharmaceutically acceptable salt or prodrug.
Included in the compounds of this invention and it is used in the method for the present invention be formula (II) compound:
Wherein:
X21And X22Independently selected from:
Hydrogen,
Cyano,
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
Re,
-OC1-6Alkyl,
-ORe,
Naphthenic base,
Heterocyclylalkyl, and
-SH；
Y1It is selected from: S, NH, NRz, S (O) and S (O)2；
R21It is selected from:
Amino,
Cyano,
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
Re,
-OC1-6Alkyl,
-ORe,
-NHRa,
-NRbRc,
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl,
- SH, and
-SRa；
R22It is selected from:
Hydrogen,
C1-6Alkyl,
Re,
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl,
By RdReplace 1-4 Heterocyclylalkyl,
-C(O)ORa, and
-C(O)NHRa；
R23It is selected from:
Hydrogen,
Aryl,
By RdReplace 1-4 aryl,
Heteroaryl, and
By RdReplace 1-4 heteroaryl；
R24It is selected from:
Hydrogen,
C1-6Alkyl,
Re,
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl,
By RdReplace 1-4 Heterocyclylalkyl,
-C(O)ORa, and
-C(O)NHRa；
R25It is selected from:
Amino,
-NHRa,
-NRbRc,
Aryl,
By RdReplace 1-4 aryl,
-OC1-6Alkyl,
-ORe,
- O aryl,
- O heteroaryl,
- SH, and
-SRa；
Wherein:
Each RaIndependently selected from
C1-6Alkyl,
Re,
Aryl,
By RdReplace 1-4 aryl,
Heteroaryl,
By RdReplace 1-4 heteroaryl,
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl, and
By RdReplace 1-4 Heterocyclylalkyl；
RbAnd RcIndependently selected from:
C1-6Alkyl,
Re,
Aryl,
By RdReplace 1-4 aryl,
Heteroaryl,
By RdReplace 1-4 heteroaryl；
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl, and
By RdReplace 1-4 Heterocyclylalkyl, or
RbAnd RcNitrogen connected to them and optional 1-3 additional hetero atoms are formed together Heterocyclylalkyl, optionally Replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
Re,
Aryl,
By RdReplace 1-4 aryl,
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl, and
By RdReplace 1-4 Heterocyclylalkyl,
C1-4Alkoxy,
The C replaced by 1-6 substituent groups independently selected from the following1-4Alkoxy: fluorine, oxo ,-OH ,-COOH ,-NH2 With-CN,
- CN,
Oxo,
- OH,
- COOH,
-NO2,
-NH2,
-N(H)C1-4Alkyl,
-N(H)Re,
-N(C1-4Alkyl)2,
SO2NH2,
SO2CH2CH3, and
SO2CH3；
Each RdIndependently selected from:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
Re,
Heteroaryl,
By RxReplace 1-4 heteroaryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Naphthenic base,
By RxReplace 1-4 naphthenic base,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Heterocyclylalkyl,
By RxReplace 1-4 Heterocyclylalkyl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Aryl,
By RxReplace 1-4 aryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
C1-4Alkoxy,
Replaced 1-4 C by fluorine1-4Alkoxy,
- O aryl,
By RxReplace 1-4-O aryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- C (O) H,
-C(O)Rzz,
- C (O) aryl,
By RzzReplace 1-4 times-C (O) aryl,
- C (O) heteroaryl,
By RzzReplace 1-4 times-C (O) heteroaryl,
- OC (O) H,
-CO(O)Rzz,
- OC (O) aryl,
By RzzReplace 1-4 times-CO (O) aryl,
- OC (O) heteroaryl,
By RzzReplace 1-4 times-OC (O) heteroaryl,
Sulfydryl,
-SRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- S (O) H,
-S(O)Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2H,
-S(O)2Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2NH2,
-S(O)2NHRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 The C that substituent group independently selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-NHS(O)2H,
-NHS(O)2Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- NHC (O) H,
-NHC(O)Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-C(O)NH2,
-C(O)NHRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-C(O)NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl, and by 1-6 The C that a substituent group independently selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- C (O) OH,
-C(O)ORx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Oxo,
Hydroxyl,
Amino,
-NHRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl,
C1-6Alkyl and the C replaced by 1-6 substituent groups independently selected from the following1-6Alkyl: fluorine, oxo ,-OH ,- COOH、-NH2With-CN,
-NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl, and by 1-6 The C that a substituent group independently selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Nitro,
Cyano,
-NHC(O)NH2,
-NHC(O)NHRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-NHC(O)NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl, and by 1-6 The C that a substituent group independently selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Each ReIndependently selected from:
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
-OC1-6Alkyl,
- the OC replaced by 1-6 substituent groups independently selected from the following1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2 With-CN, sulfydryl,
-SRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- S (O) H,
-S(O)Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2H,
-S(O)2Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Oxo,
Hydroxyl,
Amino,
-NHRxx,
Wherein RxxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-ORxy、-COOH、-CN、-OC1-5Alkyl, by fluorine and-NRxyRxzReplace 1-6 times - OC1-5Alkyl, wherein RxyAnd RxzIndependently selected from: hydrogen, aryl, C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
-NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 The C that substituent group independently selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN, guanidine radicals,
- C (O) OH,
-C(O)ORx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-C(O)NH2,
-C(O)NHRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-C(O)NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 The C that substituent group independently selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN, aryl,
By RxReplace 1-4 aryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- O aryl,
By RxReplace 1-4-O aryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Heteroaryl,
By RxReplace 1-4 heteroaryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- O heteroaryl,
By RxReplace 1-4-O heteroaryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Naphthenic base,
By RxReplace 1-4 naphthenic base,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Heterocyclylalkyl,
By RxReplace 1-4 Heterocyclylalkyl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2NH2,
-S(O)2NHRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 The C that substituent group independently selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-NHS(O)2H,
-NHS(O)2Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-NHC(O)NHRxp,
Wherein RxpReplaced selected from heteroaryl, naphthenic base, Heterocyclylalkyl and by 1-4 substituent groups independently selected from the following C1-6Alkyl :-COOH ,-NH2With-CN,
-NHC(O)NRx3Rx4,
Wherein Rx3And Rx4Be each independently selected from heteroaryl, naphthenic base, Heterocyclylalkyl and by 1-6 independently selected from Under substituent group replace C1-6Alkyl :-COOH ,-NH2With-CN,
Nitro and
Cyano；
Each RfIt independently is optionally by ReReplace 1-6 C1-6Alkyl；
Each RgIt independently is optionally by RxReplace 1-5 aryl,
Wherein RxIndependently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6It alkyl and is independently selected by 1-6 The C replaced from substituent group below1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Each RhIt independently is optionally by RxReplace 1-5 heteroaryl,
Wherein RxIndependently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6It alkyl and is independently selected by 1-6 The C replaced from substituent group below1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN, and
RzIt is selected from
C1-6Alkyl,
Re,
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl, and
By RdReplace 1-4 Heterocyclylalkyl；
RzzIt is selected from
C1-6Alkyl, and
Re；
On condition that:
R22、R23And R24At least one be hydrogen,
R22、R23And R24Not all for hydrogen and
X21And X22It is not all hydrogen；
Or its pharmaceutically acceptable salt or prodrug.
Included in the compounds of this invention and it is used in the method for the present invention be formula (III) compound:
Wherein:
X31And X32Independently selected from:
Hydrogen,
Cyano,
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
-OC1-6Alkyl,
Naphthenic base, and
-SH；
Y2It is selected from: S, NH, NRzWith S (O)；
R31It is selected from:
C1-6Alkyl,
Re1,
-OC1-6Alkyl,
-ORe1,
-NHRa1,
-NRb1Rc1,
Naphthenic base,
By Rd1Replace 1-4 naphthenic base,
- SH, and
-SRa1；
R32It is selected from:
Hydrogen,
C1-6Alkyl,
Re1,
Naphthenic base,
By Rd1Replace 1-4 naphthenic base,
Heterocyclylalkyl, and
By Rd1Replace 1-4 Heterocyclylalkyl；
R33It is selected from:
Hydrogen,
Aryl,
By Rd1Replace 1-4 aryl,
Heteroaryl, and
By Rd1Replace 1-4 heteroaryl；
R34It is selected from:
Hydrogen,
C1-6Alkyl,
Re1,
Naphthenic base,
By Rd1Replace 1-4 naphthenic base,
Heterocyclylalkyl, and
By Rd1Replace 1-4 Heterocyclylalkyl；
R35It is selected from:
Amino,
-NHRa1,
-NRb1Rc1,
Aryl,
By Rd1Replace 1-4 aryl,
-OC1-6Alkyl,
-ORe1,
- SH, and
-SRa1；
Wherein:
Each Ra1Independently selected from
C1-6Alkyl,
Re1,
Aryl,
Heteroaryl,
Naphthenic base, and
Heterocyclylalkyl；
Rb1And Rc1Independently selected from:
C1-6Alkyl,
Re1,
Aryl,
By Rd1Replace 1-4 aryl,
Heteroaryl,
By Rd1Replace 1-4 heteroaryl；
Naphthenic base,
By Rd1Replace 1-4 naphthenic base,
Heterocyclylalkyl, and
By Rd1Replace 1-4 Heterocyclylalkyl, or
Rb1And Rc1Nitrogen connected to them and optional 1-3 additional hetero atoms are formed together Heterocyclylalkyl, times Choosing is independently selected from 1-5 substituent group below and replaces:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
Re1,
Aryl,
By Rd1Replace 1-4 aryl,
Naphthenic base,
By Rd1Replace 1-4 naphthenic base,
Heterocyclylalkyl, and
By Rd1Replace 1-4 Heterocyclylalkyl,
C1-4Alkoxy,
The C replaced by 1-6 substituent groups independently selected from the following1-4Alkoxy: fluorine, oxo ,-OH ,-COOH ,-NH2 With-CN,
- CN,
Oxo,
- OH,
- COOH,
-NO2,
-NH2,
-N(H)C1-4Alkyl,
-N(H)Re1,
-N(C1-4Alkyl)2,
SO2NH2,
SO2CH2CH3, and
SO2CH3；
Each Rd1Independently selected from:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
Re1,
Heteroaryl,
By RxaReplace 1-4 heteroaryl,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
Naphthenic base,
By RxaReplace 1-4 naphthenic base,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
Heterocyclylalkyl,
By RxaReplace 1-4 Heterocyclylalkyl,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
Aryl,
By RxaReplace 1-4 aryl,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
C1-4Alkoxy,
Replaced 1-4 C by fluorine1-4Alkoxy,
- O aryl,
- C (O) H,
-C(O)Rzz,
- C (O) aryl,
- C (O) heteroaryl,
- OC (O) H,
-CO(O)Rzz,
- OC (O) aryl,
- OC (O) heteroaryl,
Sulfydryl,
-SRxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
- S (O) H,
-S(O)Rxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
-S(O)2H,
-S(O)2Rxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
-S(O)2NH2,
-S(O)2NHRxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
-NHS(O)2H,
-NHS(O)2Rxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
- NHC (O) H,
-NHC(O)Rxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
-C(O)NH2,
-C(O)NHRxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
- C (O) OH,
-C(O)ORxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
Oxo,
Hydroxyl,
Amino,
-NHRxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
Nitro,
Cyano,
-NHC(O)NH2, and
-NHC(O)NHRxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base；
Each Re1Independently selected from:
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
-OC1-6Alkyl,
- the OC replaced by 1-6 substituent groups independently selected from the following1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2 With-CN,
Sulfydryl,
-SRxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
- S (O) H,
-S(O)Rxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
-S(O)2H,
-S(O)2Rxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
Oxo,
Hydroxyl,
Amino,
-NHRxx,
Wherein RxxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-ORxy、-COOH、-CN、-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine1-5Alkane Base and-NRxyRxz, wherein RxyAnd RxzIndependently selected from: hydrogen, aryl, C1-5Alkyl and by 1-4 substitutions independently selected from the following The C that base replaces1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
-NRx1xRx2x,
Wherein Rx1xAnd Rx2xIt is each independently selected from C1-4Alkyl and replaced by 1-4 substituent groups independently selected from the following C1-4Alkyl: fluorine, oxo and-OH,
Guanidine radicals,
- C (O) OH,
-C(O)ORxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
-C(O)NHRxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base and Heterocyclylalkyl,
Aryl,
By RxaReplace 1-4 aryl,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
- O aryl,
By RxaReplace 1-4-O aryl,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
Heteroaryl,
By RxaReplace 1-4 heteroaryl,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
- O heteroaryl,
- O is by RxaReplace 1-4 heteroaryl,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
Naphthenic base,
By RxReplace 1-4 naphthenic base,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Heterocyclylalkyl,
By RxReplace 1-4 Heterocyclylalkyl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2NH2,
-S(O)2NHRxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
-NHS(O)2H,
-NHS(O)2Rxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
-NHC(O)NHRxa,
Wherein RxaSelected from heteroaryl, naphthenic base and Heterocyclylalkyl,
Nitro and
Cyano；
Each RfIt independently is optionally by Re1Replace 1-6 C1-6Alkyl；
Each RgIt independently is optionally by RxReplace 1-5 aryl,
Wherein RxIndependently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6It alkyl and is independently selected by 1-6 The C replaced from substituent group below1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Each RhIt independently is optionally by RxReplace 1-5 heteroaryl,
Wherein RxIndependently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6It alkyl and is independently selected by 1-6 The C replaced from substituent group below1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN, and
RzIt is selected from
C1-6Alkyl,
Re1,
Naphthenic base,
By Rd1Replace 1-4 naphthenic base,
Heterocyclylalkyl, and
By Rd1Replace 1-4 Heterocyclylalkyl；
RzzIt is selected from
C1-6Alkyl, and
Re1；
On condition that:
R32、R33And R34At least one be hydrogen,
R32、R33And R34Not all for hydrogen and
X31And X32It is not all hydrogen；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, in formula (III) compound, X31Or X32It is not hydrogen.
Included in the compounds of this invention and it is used in the method for the present invention be formula (IVar) compound:
Wherein:
X41arAnd X42arIndependently selected from :-CN, fluorine, chlorine, bromine and iodine；
Y4arIt is selected from: S and NH；
R41arIt is selected from:
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine,
Bromine, iodine, oxo, C1-4Alkyl oxy ,-OH ,-COOH ,-NH2、-N(H)C1-4Alkyl ,-N (C1-4Alkyl)2With-CN,
C1-4Alkyl oxy,
Replaced 1-4 C by fluorine1-4Alkyl oxy,
-N(H)C1-4Alkyl,
-N(C1-4Alkyl)2,
-SC1-4Alkyl,
Aryl,
The aryl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Fluorine, chlorine, bromine, iodine, oxo ,-OH ,-NH2With-CN,
C1-4Alkoxy,
- CN,
Oxo,
- OH,
-NO2, and
-NH2,
Heteroaryl,
The heteroaryl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Fluorine, chlorine, bromine, iodine, oxo ,-OH ,-NH2With-CN,
C1-4Alkoxy,
- CN,
Oxo,
- OH,
-NO2, and
-NH2,
Naphthenic base,
The naphthenic base replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Fluorine, chlorine, bromine, iodine, oxo ,-OH ,-NH2With-CN,
C1-4Alkoxy,
- CN,
Oxo,
- OH,
-NO2, and
-NH2；
R42arIt is selected from:
Hydrogen,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine,
Bromine, iodine, oxo ,-OH ,-NH2、-N(H)C1-4Alkyl ,-N (C1-4Alkyl)2With-CN,
Heterocyclylalkyl, and
The Heterocyclylalkyl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-OH ,-NH2 With-CN,
- NHC (O) H,
-NHC(O)Rxa1,
Wherein Rxa1Selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
C1-4Alkoxy,
- CN,
Oxo,
- OH,
-NO2, and
-NH2；
R43arIt is selected from:
Hydrogen,
C1-6Alkyl,
Aryl,
The aryl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-CN ,-OR49 With-NR46R47,
Wherein R46And R47Independently selected from: hydrogen ,-S (O)2CH3、C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR48R49Replace 1-6-OC1-5Alkane Base, wherein R48And R49Independently selected from: hydrogen, phenyl, C1-5Alkyl and replaced by 1-4 substituent groups independently selected from the following C1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
C1-4Alkoxy,
- CN,
Oxo,
- OH,
-S(O)2NH2,
-S(O)2NHCH3,
-NO2, and
-NH2,
Heteroaryl, and
The heteroaryl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-CN ,-OR49 With-NR46R47,
Wherein R46And R47Independently selected from: hydrogen ,-S (O)2CH3、C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR48R49Replace 1-6-OC1-5Alkane Base, wherein R48And R49Independently selected from: hydrogen, phenyl, C1-5Alkyl and replaced by 1-4 substituent groups independently selected from the following C1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
C1-4Alkoxy,
- CN,
Oxo,
- OH,
-S(O)2NH2,
-S(O)2NHCH3,
-NO2, and
-NH2；With
R44arAnd R45arIndependently selected from:
Hydrogen,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, Heterocyclylalkyl, C1-4Alkane Oxygroup, oxo ,-OH ,-NH2With-CN,
Heterocyclylalkyl and
The Heterocyclylalkyl replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-OH ,-NH2 With-CN,
Aryl,
C1-4Alkoxy,
- CN,
Oxo,
- OH,
- COOH,
-NO2,
-NH2, and
SO2NH2, or
R44arAnd R45arNitrogen connected to them and optional 1-3 additional hetero atoms are formed together Heterocyclylalkyl, Optionally replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, C1-4Alkoxy, oxygen Generation, phenyl, naphthenic base, Heterocyclylalkyl, methyl heterocycles alkyl ,-OH ,-NH2、-N(H)C1-4Alkyl ,-N (C1-4Alkyl)2With-CN,
Aryl,
Naphthenic base,
Heterocyclylalkyl,
The Heterocyclylalkyl replaced by 1-9 substituent groups independently selected from the following: C1-6Alkyl ,-C1-6Alkyl OH, fluorine ,- C1-6Alkyl NH2, chlorine, bromine, iodine, oxo ,-OH ,-NH2With-CN, C1-4Alkoxy,
The C replaced by 1-4 substituent groups independently selected from the following1-4Alkoxy: fluorine, oxo ,-OH ,-COOH ,-NH2 With-CN ,-CN,
Oxo,
- OH,
- COOH,
-NO2,
-NH2,
-N(H)C1-4Alkyl,
- N (H) C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, C1-4Alcoxyl Base, oxo, phenyl, naphthenic base, Heterocyclylalkyl, methyl heterocycles alkyl ,-OH ,-NH2、-N(H)C1-4Alkyl ,-N (C1-4Alkyl)2 With-CN ,-N (C1-4Alkyl)2,
SO2NH2,
SO2CH2CH3, and
SO2CH3；
On condition that:
R42arAnd R43arIt is not all hydrogen；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, in formula (IVar) compound, R44arAnd R45arIt is not hydrogen.
Suitably, in formula (IVar) compound, R42arFor-C (O) NH2。
Suitably, in formula (IVar) compound, R43arFor the virtue replaced by 1-4 substituent groups independently selected from the following Base:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-CN ,-OR49 With-NR46R47,
Wherein R46And R47Independently selected from: hydrogen ,-S (O)2CH3、C1-5It alkyl and is taken by 1-4 is independently selected from the following Replace C for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR48R49Replace 1-6-OC1-5Alkane Base, wherein R48And R49Independently selected from: hydrogen, phenyl, C1-5Alkyl and replaced by 1-4 substituent groups independently selected from the following C1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl.
Included in the compounds of this invention and it is used in the method for the present invention be formula (IV) compound:
Wherein:
X41And X42Independently selected from :-CN, fluorine, chlorine, bromine and iodine；
Y4It is selected from: S and NH；
R41It is selected from:
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo, C1-4Alkyl oxygen Base ,-OH ,-COOH ,-NH2、-N(H)C1-4Alkyl ,-N (C1-4Alkyl)2With-CN,
C1-4Alkyl oxy,
Replaced 1-4 C by fluorine1-4Alkyl oxy,
-N(H)C1-4Alkyl,
-N(C1-4Alkyl)2,
-SC1-4Alkyl,
Naphthenic base,
The naphthenic base replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Fluorine, chlorine, bromine, iodine, oxo ,-OH ,-NH2With-CN,
C1-4Alkoxy,
- CN,
Oxo,
- OH,
-NO2, and
-NH2；
R42It is selected from:
Hydrogen,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine,
Bromine, iodine, oxo ,-OH ,-NH2、-N(H)C1-4Alkyl ,-N (C1-4Alkyl)2With-CN,
Heterocyclylalkyl, and
The Heterocyclylalkyl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-OH ,-NH2 With-CN,
- NHC (O) H,
-NHC(O)Rxa1,
Wherein Rxa1Selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
C1-4Alkoxy,
- CN,
Oxo,
- OH,
-NO2, and
-NH2；
R43It is selected from:
Hydrogen,
C1-6Alkyl,
Aryl,
The aryl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-CN ,-OR49 With-NR46R47,
Wherein R46And R47Independently selected from: hydrogen ,-S (O)2CH3、C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR48R49Replace 1-6-OC1-5Alkane Base, wherein R48And R49Independently selected from: hydrogen, phenyl, C1-5Alkyl and replaced by 1-4 substituent groups independently selected from the following C1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
C1-4Alkoxy,
- CN,
Oxo,
- OH,
-S(O)2NH2,
-S(O)2NHCH3,
-NO2, and
-NH2,
Heteroaryl, and
The heteroaryl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-CN ,-OR49 With-NR46R47,
Wherein R46And R47Independently selected from: hydrogen ,-S (O)2CH3、C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR48R49Replace 1-6-OC1-5Alkane Base, wherein R48And R49Independently selected from: hydrogen, phenyl, C1-5Alkyl and replaced by 1-4 substituent groups independently selected from the following C1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
C1-4Alkoxy,
- CN,
Oxo,
- OH,
-S(O)2NH2,
-S(O)2NHCH3,
-NO2, and
-NH2；With
R44And R45Independently selected from:
Hydrogen,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine,
Bromine, iodine, Heterocyclylalkyl, C1-4Alkoxy, oxo ,-OH ,-NH2With-CN, Heterocyclylalkyl and
The Heterocyclylalkyl replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-OH ,-NH2 With-CN,
Aryl,
C1-4Alkoxy,
- CN,
Oxo,
- OH,
- COOH,
-NO2,
-NH2, and
SO2NH2, or
R44And R45Nitrogen connected to them and optional 1-3 additional hetero atoms are formed together Heterocyclylalkyl, times Choosing is replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, C1-4Alkoxy, oxygen Generation, phenyl, naphthenic base, Heterocyclylalkyl, methyl heterocycles alkyl ,-OH ,-NH2、-N(H)C1-4Alkyl ,-N (C1-4Alkyl)2With-CN,
Aryl,
Naphthenic base,
Heterocyclylalkyl,
The Heterocyclylalkyl replaced by 1-9 substituent groups independently selected from the following: C1-6Alkyl ,-C1-6Alkyl OH, fluorine ,- C1-6Alkyl NH2, chlorine, bromine, iodine, oxo ,-OH ,-NH2With-CN, C1-4Alkoxy,
The C replaced by 1-4 substituent groups independently selected from the following1-4Alkoxy: fluorine, oxo ,-OH ,-COOH ,-NH2 With-CN ,-CN,
Oxo,
- OH,
- COOH,
-NO2,
-NH2,
-N(H)C1-4Alkyl,
- N (H) C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, C1-4Alcoxyl Base, oxo, phenyl, naphthenic base, Heterocyclylalkyl, methyl heterocycles alkyl ,-OH ,-NH2、-N(H)C1-4Alkyl ,-N (C1-4Alkyl)2 With-CN ,-N (C1-4Alkyl)2,
SO2NH2,
SO2CH2CH3, and
SO2CH3；
On condition that:
R42And R43It is not all hydrogen；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, in formula (IV) compound, R44And R45It is not hydrogen.
The present invention relates to the purposes of new formula (IVaar) compound and formula (IVaar) compound in the methods of the invention:
Wherein:
X41aarAnd X42aarIndependently selected from :-CN, fluorine, chlorine, bromine and iodine；
Y4aarIt is selected from: S and NH；
R41aarIt is selected from:
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine,
Bromine, iodine, oxo, C1-4Alkyl oxy ,-OH ,-COOH ,-NH2、-N(H)C1-4Alkyl ,-N (C1-4Alkyl)2With-CN,
C1-4Alkyl oxy,
Replaced 1-4 C by fluorine1-4Alkyl oxy,
-N(H)C1-4Alkyl,
-N(C1-4Alkyl)2,
-SC1-4Alkyl,
Aryl,
The aryl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Fluorine, chlorine, bromine, iodine, oxo ,-OH ,-NH2With-CN,
C1-4Alkoxy,
- CN,
Oxo,
- OH,
-NO2, and
-NH2,
Heteroaryl,
The heteroaryl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Fluorine, chlorine, bromine, iodine, oxo ,-OH ,-NH2With-CN,
C1-4Alkoxy,
- CN,
Oxo,
- OH,
-NO2, and
-NH2,
Naphthenic base,
The naphthenic base replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Fluorine, chlorine, bromine, iodine, oxo ,-OH ,-NH2With-CN,
C1-4Alkoxy,
- CN,
Oxo,
- OH,
-NO2, and
-NH2；
R42aarIt is selected from:
Hydrogen,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine,
Bromine, iodine, oxo ,-OH ,-NH2、-N(H)C1-4Alkyl ,-N (C1-4Alkyl)2With-CN,
Heterocyclylalkyl, and
The Heterocyclylalkyl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-OH ,-NH2 With-CN,
- NHC (O) H,
-NHC(O)Rxa1,
Wherein Rxa1Selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
C1-4Alkoxy,
- CN,
Oxo,
- OH,
-NO2, and
-NH2；
R43aarIt is selected from:
Hydrogen,
C1-6Alkyl,
Aryl,
The aryl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-CN ,-OR49 With-NR46R47,
Wherein R46And R47Independently selected from: hydrogen ,-S (O)2CH3、C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR48R49Replace 1-6-OC1-5Alkane Base, wherein R48And R49Independently selected from: hydrogen, phenyl, C1-5Alkyl and replaced by 1-4 substituent groups independently selected from the following C1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
C1-4Alkoxy,
- CN,
Oxo,
- OH,
-S(O)2NH2,
-S(O)2NHCH3,
-NO2, and
-NH2,
Heteroaryl, and
The heteroaryl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkane
Base: fluorine, chlorine, bromine, iodine, oxo ,-CN ,-OR49With-NR46R47,
Wherein R46And R47Independently selected from: hydrogen ,-S (O)2CH3、C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR48R49Replace 1-6-OC1-5Alkane Base, wherein R48And R49Independently selected from: hydrogen, phenyl, C1-5Alkyl and replaced by 1-4 substituent groups independently selected from the following C1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
C1-4Alkoxy,
- CN,
Oxo,
- OH,
-S(O)2NH2,
-S(O)2NHCH3,
-NO2, and
-NH2；With
R44aarAnd R45aarIndependently selected from:
Hydrogen,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, Heterocyclylalkyl, C1-4Alkane Oxygroup, oxo ,-OH ,-NH2With-CN,
Heterocyclylalkyl and
The Heterocyclylalkyl replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-OH ,-NH2 With-CN,
Aryl,
C1-4Alkoxy,
The C replaced by 1-4 substituent groups independently selected from the following1-4Alkoxy: fluorine, oxo ,-OH ,-COOH ,-NH2 With-CN,
- CN,
Oxo,
- OH,
- COOH,
-NO2,
-NH2, and
SO2NH2, or
R44aarAnd R45aarNitrogen connected to them and optional 1-3 additional hetero atoms are formed together Heterocyclylalkyl, It is optionally replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, C1-4Alkoxy, oxygen Generation, phenyl,
Naphthenic base, Heterocyclylalkyl, methyl heterocycles alkyl ,-OH ,-NH2、
-N(H)C1-4Alkyl ,-N (C1-4Alkyl)2With-CN,
Aryl,
Naphthenic base,
Heterocyclylalkyl,
The Heterocyclylalkyl replaced by 1-9 substituent groups independently selected from the following: C1-6Alkyl ,-C1-6Alkyl OH, fluorine ,- C1-6Alkyl NH2, chlorine, bromine, iodine, oxo ,-OH ,-NH2With-CN,
C1-4Alkoxy,
- CN,
Oxo,
- OH,
- COOH,
-NO2,
-NH2,
-N(H)C1-4Alkyl,
- N (H) C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, C1-4Alcoxyl Base, oxo, phenyl, naphthenic base, Heterocyclylalkyl, methyl heterocycles alkyl ,-OH ,-NH2、-N(H)C1-4Alkyl ,-N (C1-4Alkyl)2 With-CN,
-N(C1-4Alkyl)2,
SO2NH2,
SO2CH2CH3, and
SO2CH3；
On condition that:
R42aarAnd R43aarIt is not all hydrogen, and
R44aarAnd R45aarIt is not all hydrogen；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, in formula (IVaar) compound, R44aarAnd R45aarIt is not hydrogen.
Suitably, in formula (IVaar) compound, R42aarFor-C (O) NH2。
Suitably, in formula (IVaar) compound, R43aarFor what is replaced by 1-4 substituent groups independently selected from the following Aryl:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-CN ,-OR49 With-NR46R47,
Wherein R46And R47Independently selected from: hydrogen ,-S (O)2CH3、C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR48R49Replace 1-6-OC1-5Alkane Base, wherein R48And R49Independently selected from: hydrogen, phenyl, C1-5Alkyl and replaced by 1-4 substituent groups independently selected from the following C1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl.
The present invention relates to the purposes of new formula (IVa) compound and formula (IVa) compound in the methods of the invention:
Wherein:
X41aAnd X42aIndependently selected from :-CN, fluorine, chlorine, bromine and iodine；
Y4aIt is selected from: S and NH；
R41aIt is selected from:
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo, C1-4Alkyl oxygen Base ,-OH ,-COOH ,-NH2、-N(H)C1-4Alkyl ,-N (C1-4Alkyl)2With-CN,
C1-4Alkyl oxy,
Replaced 1-4 C by fluorine1-4Alkyl oxy,
-N(H)C1-4Alkyl,
-N(C1-4Alkyl)2,
-SC1-4Alkyl,
Naphthenic base,
The naphthenic base replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Fluorine, chlorine, bromine, iodine, oxo ,-OH ,-NH2With-CN,
C1-4Alkoxy,
- CN,
Oxo,
- OH,
-NO2, and
-NH2；
R42aIt is selected from:
Hydrogen,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-OH ,- NH2、-N(H)C1-4Alkyl ,-N (C1-4Alkyl)2With-CN,
Heterocyclylalkyl, and
The Heterocyclylalkyl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-OH ,-NH2 With-CN,
- NHC (O) H,
-NHC(O)Rxa1,
Wherein Rxa1Selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
C1-4Alkoxy,
- CN,
Oxo,
- OH,
-NO2, and
-NH2；
R43aIt is selected from:
Hydrogen,
C1-6Alkyl,
Aryl,
The aryl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-CN ,-OR49 With-NR46R47,
Wherein R46And R47Independently selected from: hydrogen ,-S (O)2CH3、C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR48R49Replace 1-6-OC1-5Alkane Base, wherein R48And R49Independently selected from: hydrogen, phenyl, C1-5Alkyl and replaced by 1-4 substituent groups independently selected from the following C1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
C1-4Alkoxy,
- CN,
Oxo,
- OH,
-S(O)2NH2,
-S(O)2NHCH3,
-NO2, and
-NH2,
Heteroaryl, and
The heteroaryl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-CN ,-OR49 With-NR46R47,
Wherein R46And R47Independently selected from: hydrogen ,-S (O)2CH3、C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR48R49Replace 1-6-OC1-5Alkane Base, wherein R48And R49Independently selected from: hydrogen, phenyl, C1-5Alkyl and replaced by 1-4 substituent groups independently selected from the following C1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
C1-4Alkoxy,
- CN,
Oxo,
- OH,
-S(O)2NH2,
-S(O)2NHCH3,
-NO2, and
-NH2；With
R44aAnd R45aIndependently selected from:
Hydrogen,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, Heterocyclylalkyl, C1-4Alkane Oxygroup, oxo ,-OH ,-NH2With-CN, Heterocyclylalkyl and
The Heterocyclylalkyl replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-OH ,-NH2 With-CN, aryl,
C1-4Alkoxy,
The C replaced by 1-4 substituent groups independently selected from the following1-4Alkoxy: fluorine, oxo ,-OH ,-COOH ,-NH2 With-CN,
- CN,
Oxo,
- OH,
- COOH,
-NO2,
-NH2, and
SO2NH2, or
R44aAnd R45aNitrogen connected to them and optional 1-3 additional hetero atoms are formed together Heterocyclylalkyl, Optionally replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, C1-4Alkoxy, oxygen Generation, phenyl, naphthenic base, Heterocyclylalkyl, methyl heterocycles alkyl ,-OH ,-NH2、-N(H)C1-4Alkyl ,-N (C1-4Alkyl)2With-CN,
Aryl,
Naphthenic base,
Heterocyclylalkyl,
The Heterocyclylalkyl replaced by 1-9 substituent groups independently selected from the following: C1-6Alkyl ,-C1-6Alkyl OH, fluorine ,- C1-6Alkyl NH2, chlorine, bromine, iodine, oxo ,-OH ,-NH2With-CN,
C1-4Alkoxy,
- CN,
Oxo,
- OH,
- COOH,
-NO2,
-NH2,
-N(H)C1-4Alkyl,
- N (H) C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, C1-4Alcoxyl Base, oxo, phenyl, naphthenic base, Heterocyclylalkyl, methyl heterocycles alkyl ,-OH ,-NH2,-N (H) C1-4Alkyl ,-N (C1-4Alkyl)2 With-CN,
-N(C1-4Alkyl)2,
SO2NH2,
SO2CH2CH3, and
SO2CH3；
On condition that:
R42aAnd R43aIt is not all hydrogen, and
R44aAnd R45aIt is not all hydrogen；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, in formula (IVa) compound, R44aAnd R45aIt is not hydrogen.
Included in the compounds of this invention and it is used in the method for the present invention be formula (V) compound:
Wherein:
X51And X52Independently selected from :-CN, fluorine and chlorine；
Y5It is selected from: S and NH；
R50It is selected from:
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine and chlorine,
-N(H)C1-4Alkyl,
-N(C1-4Alkyl)2,
-SC1-4Alkyl,
C1-4Alkyl oxy,
Naphthenic base,
The naphthenic base replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH,
C1-6Alkyl, and
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Fluorine and chlorine；
R51It is selected from:
Hydrogen,
C1-6Alkyl,
-C(O)NHR55, wherein R55It is selected from: hydrogen, C1-6Alkyl is replaced by 1-9 substituent groups independently selected from the following C1-6Alkyl: fluorine and chlorine,
Heterocyclylalkyl, and
The Heterocyclylalkyl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
C1-6Alkyl,
The C replaced by 1-6 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, oxo ,-OH ,-NH2With- CN,
- NHC (O) H,
-NHC(O)Rxa2,
Wherein Rxa2Selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
C1-4Alkoxy,
- CN,
Oxo,
- OH, and
-NH2；
R52It is selected from:
Hydrogen,
C1-6Alkyl,
Aryl,
The aryl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-CN ,-OR59 With-NR56R57,
Wherein R56And R57Independently selected from: hydrogen ,-S (O)2CH3、C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR58R59Replace 1-6-OC1-5Alkane Base, wherein R58And R59Independently selected from: hydrogen, phenyl, C1-5Alkyl and replaced by 1-4 substituent groups independently selected from the following C1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
Oxo,
- CN,
-S(O)2NH2,
-S(O)2NHCH3,
-OH；
Heteroaryl, and
The heteroaryl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-CN ,-OR59 With-NR56R57,
Wherein R56And R57Independently selected from: hydrogen ,-S (O)2CH3、C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR58R59Replace 1-6-OC1-5Alkane Base, wherein R58And R59Independently selected from: hydrogen, phenyl, C1-5Alkyl and replaced by 1-4 substituent groups independently selected from the following C1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
Oxo,
-S(O)2NH2,
-S(O)2NHCH3,
-OH；With
R53And R54Independently selected from:
Hydrogen,
C1-6Alkyl,
The C replaced by 1-6 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, oxo, Heterocyclylalkyl, C1-4Alkane Oxygroup ,-OH and-NH2,
Heterocyclylalkyl, and
The Heterocyclylalkyl replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine and chlorine,
C1-4Alkoxy, and
- OH, or
R53And R54Nitrogen connected to them and optional 1-3 additional hetero atoms are formed together Heterocyclylalkyl, times Choosing is replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, C1-4Alkoxy, oxo, phenyl, Naphthenic base, Heterocyclylalkyl, methyl heterocycles alkyl ,-OH ,-NH2、-N(H)C1-4Alkyl ,-N (C1-4Alkyl)2With-CN,
Heterocyclylalkyl,
The Heterocyclylalkyl replaced by 1-9 substituent groups independently selected from the following: C1-6Alkyl ,-C1-6Alkyl OH, fluorine ,- C1-6Alkyl NH2, chlorine, oxo and-OH,
C1-4Alkoxy,
The C replaced by 1-4 substituent groups independently selected from the following1-4Alkoxy: fluorine, oxo ,-OH ,-COOH ,-NH2 With-CN,
- CN,
Oxo,
- OH,
- COOH,
-NH2,
-N(H)C1-4Alkyl,
- N (H) C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, C1-4Alkoxy, oxo, Phenyl, naphthenic base, Heterocyclylalkyl, methyl heterocycles alkyl ,-OH ,-NH2、-N(H)C1-4Alkyl ,-N (C1-4Alkyl)2With-CN, and-N (C1-4Alkyl)2；
On condition that:
R51And R52It is not all hydrogen；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, in formula (V) compound, R53And R54It is not hydrogen.
The present invention relates to the purposes of new formula (Vaar) compound and formula (Vaar) compound in the methods of the invention:
Wherein:
X51aarAnd X52aarIndependently selected from :-CN, fluorine and chlorine；
Y5aarIt is selected from: S and NH；
R50aarIt is selected from:
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine and chlorine,
-N(H)C1-4Alkyl,
-N(C1-4Alkyl)2,
-SC1-4Alkyl,
C1-4Alkyl oxy,
Aryl,
The alkyl replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH,
C1-6Alkyl, and
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Fluorine and chlorine,
Heteroaryl,
The miscellaneous alkyl replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH,
C1-6Alkyl, and
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Fluorine and chlorine,
Naphthenic base,
The naphthenic base replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH,
C1-6Alkyl, and
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Fluorine and chlorine；
R51aarIt is selected from:
Hydrogen,
C1-6Alkyl,
-C(O)NHR55, wherein R55It is selected from: hydrogen, C1-6Alkyl is replaced by 1-9 substituent groups independently selected from the following C1-6Alkyl: fluorine and chlorine,
Heterocyclylalkyl, and
The Heterocyclylalkyl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
C1-6Alkyl,
The C replaced by 1-6 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, oxo ,-OH ,-NH2With- CN,
- NHC (O) H,
-NHC(O)Rxa2,
Wherein Rxa2Selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
C1-4Alkoxy,
- CN,
Oxo,
- OH, and
-NH2；
R52aarIt is selected from:
Hydrogen,
C1-6Alkyl,
Aryl,
The aryl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-CN ,-OR59 With-NR56R57,
Wherein R56And R57Independently selected from: hydrogen ,-S (O)2CH3、C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR58R59Replace 1-6-OC1-5Alkane Base, wherein R58And R59Independently selected from: hydrogen, phenyl, C1-5Alkyl and replaced by 1-4 substituent groups independently selected from the following C1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
Oxo,
- CN,
-S(O)2NH2,
-S(O)2NHCH3,
- OH,
Heteroaryl, and
The heteroaryl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-CN ,-OR59 With-NR56R57,
Wherein R56And R57Independently selected from: hydrogen ,-S (O)2CH3、C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR58R59Replace 1-6-OC1-5Alkane Base, wherein R58And R59Independently selected from: hydrogen, phenyl, C1-5Alkyl and replaced by 1-4 substituent groups independently selected from the following C1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
Oxo,
-S(O)2NH2,
-S(O)2NHCH3,
-OH；With
R53aarAnd R54aarIndependently selected from:
Hydrogen,
C1-6Alkyl,
The C replaced by 1-6 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, oxo, Heterocyclylalkyl, C1-4Alkane Oxygroup ,-OH and-NH2,
Heterocyclylalkyl, and
The Heterocyclylalkyl replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine and chlorine,
C1-4Alkoxy, and
- OH, or
R53aarAnd R54aarNitrogen connected to them and optional 1-3 additional hetero atoms form Heterocyclylalkyl, times Choosing is replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, C1-4Alkoxy, oxo, phenyl, Naphthenic base, Heterocyclylalkyl, methyl heterocycles alkyl ,-OH ,-NH2,-N (H) C1-4Alkyl ,-N (C1-4Alkyl)2With-CN,
Heterocyclylalkyl,
The Heterocyclylalkyl replaced by 1-9 substituent groups independently selected from the following: C1-6Alkyl ,-C1-6Alkyl OH, fluorine ,- C1-6Alkyl NH2, chlorine, oxo and-OH,
C1-4Alkoxy,
The C replaced by 1-4 substituent groups independently selected from the following1-4Alkoxy: fluorine, oxo ,-OH ,-COOH ,-NH2 With-CN,
- CN,
Oxo,
- OH,
- COOH,
-NH2,
-N(H)C1-4Alkyl,
- N (H) C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, C1-4Alkoxy, oxo, Phenyl, naphthenic base, Heterocyclylalkyl, methyl heterocycles alkyl ,-OH ,-NH2、-N(H)C1-4Alkyl ,-N (C1-4Alkyl)2With-CN, and-N (C1-4Alkyl)2；
On condition that:
R51aarAnd R52aarIt is not all hydrogen, and
R53aarAnd R54aarIt is not all hydrogen；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, in formula (Vaar) compound, R53aarAnd R54aarIt is not hydrogen.
Suitably, in formula (Vaar) compound, R51aarFor-C (O) NH2。
Suitably, in formula (Vaar) compound, R52aarFor the virtue replaced by 1-4 substituent groups independently selected from the following Base:
Fluorine,
Chlorine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-CN ,-OR59 With-NR56R57,
Wherein R56And R57Independently selected from: hydrogen ,-S (O)2CH3、C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR58R59Replace 1-6-OC1-5Alkane Base, wherein R58And R59Independently selected from: hydrogen, phenyl, C1-5Alkyl and replaced by 1-4 substituent groups independently selected from the following C1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl.
The present invention relates to the purposes of new formula (Va) compound and formula (Va) compound in the methods of the invention:
Wherein:
X51aAnd X52aIndependently selected from :-CN, fluorine and chlorine；
Y5aIt is selected from: S and NH；
R50aIt is selected from:
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine and chlorine,
-N(H)C1-4Alkyl,
-N(C1-4Alkyl)2,
-SC1-4Alkyl,
C1-4Alkyl oxy,
Naphthenic base,
The naphthenic base replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH,
C1-6Alkyl, and
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Fluorine and chlorine；
R51aIt is selected from:
Hydrogen,
C1-6Alkyl,
-C(O)NHR55, wherein R55It is selected from: hydrogen, C1-6Alkyl is replaced by 1-9 substituent groups independently selected from the following C1-6Alkyl: fluorine and chlorine,
Heterocyclylalkyl, and
The Heterocyclylalkyl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
C1-6Alkyl,
The C replaced by 1-6 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, oxo ,-OH ,-NH2With- CN,
- NHC (O) H,
-NHC(O)Rxa2,
Wherein Rxa2Selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
C1-4Alkoxy,
- CN,
Oxo,
- OH, and
-NH2；
R52aIt is selected from:
Hydrogen,
C1-6Alkyl,
Aryl,
The aryl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-CN ,-OR59 With-NR56R57,
Wherein R56And R57Independently selected from: hydrogen ,-S (O)2CH3、C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR58R59Replace 1-6-OC1-5Alkane Base, wherein R58And R59Independently selected from: hydrogen, phenyl, C1-5Alkyl and replaced by 1-4 substituent groups independently selected from the following C1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
Oxo,
- CN,
-S(O)2NH2,
-S(O)2NHCH3,
- OH,
Heteroaryl, and
The heteroaryl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-CN ,-OR59 With-NR56R57,
Wherein R56And R57Independently selected from: hydrogen ,-S (O)2CH3、C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR58R59Replace 1-6-OC1-5Alkane Base, wherein R58And R59Independently selected from: hydrogen, phenyl, C1-5Alkyl and replaced by 1-4 substituent groups independently selected from the following C1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
Oxo,
-S(O)2NH2,
-S(O)2NHCH3,
-OH；With
R53aAnd R54aIndependently selected from:
Hydrogen,
C1-6Alkyl,
The C replaced by 1-6 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine,
Oxo, Heterocyclylalkyl, C1-4Alkoxy ,-OH and-NH2,
Heterocyclylalkyl, and
The Heterocyclylalkyl replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine and chlorine,
C1-4Alkoxy, and
- OH, or
R53aAnd R54aNitrogen connected to them and optional 1-3 additional hetero atoms are formed together Heterocyclylalkyl, Optionally replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, C1-4Alkoxy, oxo, phenyl, Naphthenic base, Heterocyclylalkyl, methyl heterocycles alkyl ,-OH ,-NH2、-N(H)C1-4Alkyl ,-N (C1-4Alkyl)2, and-CN,
Heterocyclylalkyl,
The Heterocyclylalkyl replaced by 1-9 substituent groups independently selected from the following: C1-6Alkyl ,-C1-6Alkyl OH, fluorine ,- C1-6Alkyl NH2, chlorine, oxo and-OH,
C1-4Alkoxy,
The C replaced by 1-4 substituent groups independently selected from the following1-4Alkoxy: fluorine, oxo ,-OH ,-COOH ,-NH2 With-CN,
- CN,
Oxo,
- OH,
- COOH,
-NH2,
-N(H)C1-4Alkyl,
- N (H) C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, C1-4Alkoxy, oxo, Phenyl, naphthenic base, Heterocyclylalkyl, methyl heterocycles alkyl ,-OH ,-NH2、-N(H)C1-4Alkyl ,-N (C1-4Alkyl)2With-CN, and
-N(C1-4Alkyl)2；
On condition that:
R51aAnd R52aIt is not all hydrogen, and
R53aAnd R54aIt is not all hydrogen；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, in formula (Va) compound, R53aAnd R54aIt is not hydrogen.
Included in the compounds of this invention and it is used in the method for the present invention be formula (VI) compound:
Wherein:
Y6It is selected from: S and NH；
R60It is selected from:
C1-3Alkyl,
The C replaced by 1-6 substituent groups independently selected from the following1-3Alkyl: fluorine and chlorine,
-N(H)C1-3Alkyl,
-N(C1-3Alkyl)2,
-SC1-4Alkyl,
C1-3Alkyl oxy,
Naphthenic base,
The naphthenic base replaced by 1-3 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH, and
C1-3Alkyl；
R61It is selected from:
Hydrogen,
-C(O)NH2,
Heterocyclylalkyl, and
The Heterocyclylalkyl replaced by 1-4 substituent groups independently selected from the following:
Oxo,
The C replaced by 1-4 substituent groups independently selected from the following1-4Alkyl: fluorine, oxo and-NH2,
- NHC (O) H, and
-NHC(O)Rxa3,
Wherein Rxa3Selected from C1-6Alkyl and 1-6 is replaced by fluorine
Secondary C1-6Alkyl；
R62It is selected from:
Hydrogen,
C1-3Alkyl,
Aryl,
The aryl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
C1-6Alkyl,
The C replaced by 1-5 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-CN ,-OR69 With-NR66R67,
Wherein R66And R67Independently selected from: hydrogen ,-S (O)2CH3、C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR68R69Replace 1-6-OC1-5Alkane Base, wherein R68And R69Independently selected from: hydrogen, phenyl, C1-5Alkyl and replaced by 1-4 substituent groups independently selected from the following C1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
- CN,
-S(O)2NH2, and
-S(O)2NHCH3,
Heteroaryl, and
The heteroaryl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
C1-6Alkyl,
The C replaced by 1-5 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-CN ,-OR69 With-NR66R67, wherein R66And R67Independently selected from: hydrogen ,-S (O)2CH3、C1-5Alkyl and independently selected from the following by 1-4 The C that substituent group replaces1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR68R69Replace 1-6-OC1-5 Alkyl, wherein R68And R69Independently selected from: hydrogen, phenyl, C1-5Alkyl and replaced by 1-4 substituent groups independently selected from the following C1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
-S(O)2NH2, and
-S(O)2NHCH3；With
R63And R64Independently selected from:
Hydrogen,
C1-4Alkyl,
The C replaced by 1-6 substituent groups independently selected from the following1-4Alkyl: fluorine, Heterocyclylalkyl, oxo ,-NH2、C1-4 Alkoxy and-OH,
Heterocyclylalkyl, and
The Heterocyclylalkyl replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH, and
C1-6Alkyl, or
R63And R64Nitrogen connected to them and optional 1-3 additional hetero atoms are formed together Heterocyclylalkyl, times Choosing is replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, C1-4Alkoxy, oxo, phenyl, Naphthenic base, Heterocyclylalkyl, methyl heterocycles alkyl ,-OH ,-NH2、-N(H)C1-4Alkyl ,-N (C1-4Alkyl)2With-CN,
Heterocyclylalkyl,
The Heterocyclylalkyl replaced by 1-9 substituent groups independently selected from the following: C1-6Alkyl ,-C1-6Alkyl OH, fluorine, chlorine, Oxo and-OH,
C1-4Alkoxy,
The C replaced by 1-4 substituent groups independently selected from the following1-4Alkoxy: fluorine, oxo ,-OH ,-COOH ,-NH2 With-CN,
Oxo,
-NH2,
-N(H)C1-4Alkyl,
- N (H) C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Fluorine, chlorine, C1-4Alkoxy, oxo, phenyl, naphthenic base, Heterocyclylalkyl, methyl heterocycles alkyl ,-OH ,-NH2,-N (H) C1-4Alkyl ,-N (C1-4Alkyl)2, and-CN, and
-N(C1-4Alkyl)2；
On condition that:
R61And R62It is not all hydrogen；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, in formula (VI) compound, R63And R64It is not hydrogen.
The present invention relates to new formula (VIaar) compound and formula (VIaar) compound purposes in the methods of the invention:
Wherein:
Y6aarIt is selected from: S and NH；
R60aarIt is selected from:
C1-3Alkyl,
The C replaced by 1-6 substituent groups independently selected from the following1-3Alkyl: fluorine and chlorine,
-N(H)C1-3Alkyl,
-N(C1-3Alkyl)2,
-SC1-4Alkyl,
C1-3Alkyl oxy,
Aryl,
The aryl replaced by 1-3 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH, and
C1-3Alkyl,
Heteroaryl,
The heteroaryl replaced by 1-3 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH, and
C1-3Alkyl,
Naphthenic base,
The naphthenic base replaced by 1-3 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH, and
C1-3Alkyl；
R61aarIt is selected from:
Hydrogen,
-C(O)NH2,
Heterocyclylalkyl, and
The Heterocyclylalkyl replaced by 1-4 substituent groups independently selected from the following:
Oxo,
The C replaced by 1-4 substituent groups independently selected from the following1-4Alkyl: fluorine, oxo and-NH2,
- NHC (O) H, and
-NHC(O)Rxa3,
Wherein Rxa3Selected from C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkyl；
R62aarIt is selected from:
Hydrogen,
C1-3Alkyl,
Aryl,
The aryl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
C1-6Alkyl,
The C replaced by 1-5 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-CN ,-OR69 With-NR66R67,
Wherein R66And R67Independently selected from: hydrogen ,-S (O)2CH3、C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR68R69Replace 1-6-OC1-5Alkane Base, wherein R68And R69Independently selected from: hydrogen, phenyl, C1-5Alkyl and replaced by 1-4 substituent groups independently selected from the following C1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
- CN,
-S(O)2NH2, and
-S(O)2NHCH3,
Heteroaryl, and
The heteroaryl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
C1-6Alkyl,
The C replaced by 1-5 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-CN ,-OR69 With-NR66R67,
Wherein R66And R67Independently selected from: hydrogen ,-S (O)2CH3、C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR68R69Replace 1-6-OC1-5Alkane Base, wherein R68And R69Independently selected from: hydrogen, phenyl, C1-5Alkyl and replaced by 1-4 substituent groups independently selected from the following C1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
-S(O)2NH2, and
-S(O)2NHCH3；
R63aarAnd R64aarIndependently selected from:
Hydrogen,
C1-4Alkyl,
The C replaced by 1-6 substituent groups independently selected from the following1-4Alkyl: fluorine, Heterocyclylalkyl, oxo ,-NH2, C1-4 Alkoxy and-OH,
Heterocyclylalkyl, and
The Heterocyclylalkyl replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH, and
C1-6Alkyl, or
R63aarAnd R64aarNitrogen connected to them and optional 1-3 additional hetero atoms are formed together Heterocyclylalkyl, It is optionally replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, C1-4Alkoxy, oxo, phenyl, Naphthenic base, Heterocyclylalkyl, methyl heterocycles alkyl ,-OH ,-NH2、-N(H)C1-4Alkyl ,-N (C1-4Alkyl)2With-CN,
Heterocyclylalkyl,
The Heterocyclylalkyl replaced by 1-9 substituent groups independently selected from the following: C1-6Alkyl ,-C1-6Alkyl OH, fluorine, chlorine, Oxo and-OH,
C1-4Alkoxy,
The C replaced by 1-4 substituent groups independently selected from the following1-4Alkoxy: fluorine, oxo ,-OH ,-COOH ,-NH2 With-CN,
Oxo,
-NH2,
-N(H)C1-4Alkyl,
- N (H) C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Fluorine, chlorine, C1-4Alkoxy, oxo, phenyl, naphthenic base, Heterocyclylalkyl, methyl heterocycles alkyl ,-OH ,-NH2、-N(H) C1-4Alkyl ,-N (C1-4Alkyl)2With-CN, and
-N(C1-4Alkyl)2；
On condition that:
R61aarAnd R62aarIt is not all hydrogen, and
R63aarAnd R64aarIt is not all hydrogen；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, in formula (VIaar) compound, R63aarAnd R64aarIt is not hydrogen.
Suitably, in formula (VIaar) compound, R61aarFor-C (O) NH2。
Suitably, in formula (VIaar) compound, R62aarFor what is replaced by 1-4 substituent groups independently selected from the following Aryl:
Fluorine,
Chlorine,
C1-6Alkyl,
The C replaced by 1-5 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-CN ,-OR69 With-NR66R67,
Wherein R66And R67Independently selected from: hydrogen ,-S (O)2CH3、C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR68R69Replace 1-6-OC1-5Alkane Base, wherein R68And R69Independently selected from: hydrogen, phenyl, C1-5Alkyl and replaced by 1-4 substituent groups independently selected from the following C1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl.
The present invention relates to the purposes of new formula (VIa) compound and formula (VIa) compound in the methods of the invention:
Wherein:
Y6aIt is selected from: S and NH；
R60aIt is selected from:
C1-3Alkyl,
The C replaced by 1-6 substituent groups independently selected from the following1-3Alkyl: fluorine and chlorine,
-N(H)C1-3Alkyl,
-N(C1-3Alkyl)2,
-SC1-4Alkyl,
C1-3Alkyl oxy,
Naphthenic base,
The naphthenic base replaced by 1-3 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH, and
C1-3Alkyl；
R61aIt is selected from:
Hydrogen,
-C(O)NH2,
Heterocyclylalkyl, and
The Heterocyclylalkyl replaced by 1-4 substituent groups independently selected from the following:
Oxo,
The C replaced by 1-4 substituent groups independently selected from the following1-4Alkyl: fluorine, oxo and-NH2,
- NHC (O) H, and
-NHC(O)Rxa3,
Wherein Rxa3Selected from C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkyl；
R62aIt is selected from:
Hydrogen,
C1-3Alkyl,
Aryl,
The aryl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
C1-6Alkyl,
The C replaced by 1-5 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-CN ,-OR69 With-NR66R67,
Wherein R66And R67Independently selected from: hydrogen ,-S (O)2CH3、C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR68R69Replace 1-6-OC1-5Alkane Base, wherein R68And R69Independently selected from: hydrogen, phenyl, C1-5Alkyl and replaced by 1-4 substituent groups independently selected from the following C1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
- CN,
-S(O)2NH2, and
-S(O)2NHCH3,
Heteroaryl, and
The heteroaryl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
C1-6Alkyl,
The C replaced by 1-5 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-CN ,-OR69 With-NR66R67,
Wherein R66And R67Independently selected from: hydrogen ,-S (O)2CH3、C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR68R69Replace 1-6-OC1-5Alkane Base, wherein R68And R69Independently selected from: hydrogen, phenyl, C1-5Alkyl and replaced by 1-4 substituent groups independently selected from the following C1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
-S(O)2NH2, and
-S(O)2NHCH3；
R63aAnd R64aIndependently selected from:
Hydrogen,
C1-4Alkyl,
The C replaced by 1-6 substituent groups independently selected from the following1-4Alkyl: fluorine, Heterocyclylalkyl, oxo ,-NH2、C1-4 Alkoxy and-OH,
Heterocyclylalkyl, and
The Heterocyclylalkyl replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH, and
C1-6Alkyl, or
R63aAnd R64aNitrogen connected to them and optional 1-3 additional hetero atoms are formed together Heterocyclylalkyl, Optionally replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, C1-4Alkoxy, oxo, phenyl, Naphthenic base, Heterocyclylalkyl, methyl heterocycles alkyl ,-OH ,-NH2、-N(H)C1-4Alkyl ,-N (C1-4Alkyl)2With-CN,
Heterocyclylalkyl,
The Heterocyclylalkyl replaced by 1-9 substituent groups independently selected from the following: C1-6Alkyl ,-C1-6Alkyl OH, fluorine, chlorine, Oxo and-OH,
C1-4Alkoxy,
The C replaced by 1-4 substituent groups independently selected from the following1-4Alkoxy: fluorine, oxo ,-OH ,-COOH ,-NH2 With-CN,
Oxo,
-NH2,
-N(H)C1-4Alkyl,
- N (H) C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Fluorine, chlorine, C1-4Alkoxy, oxo, phenyl, naphthenic base, Heterocyclylalkyl, methyl heterocycles alkyl ,-OH ,-NH2,-N (H) C1-4Alkyl ,-N (C1-4Alkyl)2With-CN, and
-N(C1-4Alkyl)2；
On condition that:
R61aAnd R62aIt is not all hydrogen, and
R63aAnd R64aIt is not all hydrogen；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, in formula (VIa) compound, R63aAnd R64aIt is not hydrogen.
Included in the compounds of this invention and it is used in the method for the present invention be formula (VII) compound:
Wherein:
Y7It is selected from: S and NH；
R70It is selected from:
Ethyl,
-CH2CF3,
-NCH3,
-SCH3,
Ethyoxyl, and
Cyclopropyl；
R71It is selected from:
Hydrogen,
-C(O)NH2,
Heterocyclylalkyl, and
By oxo ,-C (O) CH3Or-NHC (O) CH3Substituted Heterocyclylalkyl；
R77It is selected from:
Hydrogen,
C1-3Alkyl, and
Aryl,
The aryl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
C1-6Alkyl,
The C replaced by 1-3 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-CN ,-OR79 With-NR76R77,
Wherein R76And R77Independently selected from: hydrogen ,-S (O)2CH3、C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR78R79Replace 1-6-OC1-5Alkane Base, wherein R78And R79Independently selected from: hydrogen, phenyl, C1-5Alkyl and replaced by 1-4 substituent groups independently selected from the following C1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
- CN,
S(O)2NH2, and
-S(O)2NHCH3,
Pyridyl group,
Thiazolyl, and
By-C (O) CH3Or-NHC (O) CH3Substituted thiazolyl；
R72And R73Independently selected from:
Hydrogen,
C1-3Alkyl,
The C replaced by 1-3 substituent groups independently selected from the following1-3Alkyl :-OH, oxo ,-NH2, morpholino and methoxy Base,
5- oxa- -2- azaspiro [3.4] octyl, and
8- azabicyclo [3.2.1] octyl, or
R72And R73Nitrogen connected to them and optional 1-3 additional hetero atoms are formed together Heterocyclylalkyl, select From:
Pyrrolidinyl,
Piperidyl,
Isosorbide-5-Nitrae-Diazesuberane base,
Piperazinyl,
2,9- diaza spiros [5.5] undecyl,
2,8- diaza spiros [4.5] decyl,
Hexahydro -1H- pyrrolo- [1,2a] [Isosorbide-5-Nitrae] diaza cycloheptatriene base,
Morpholinyl,
1- oxa- -6- azaspiro [3.4] octyl,
1,7- diaza spiro [3.5] nonyl,
2,7- diaza spiros [3.5] nonyl,
2,6- diaza spiros [3.4] octyl,
Azetidinyl,
1,8- diaza spiro [4.5] decyl, and
5- oxa- -2- azaspiro [3.4] octyl,
All of which is optionally replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Oxo,
- OH,
-CH3,
-CH2OH,
Methoxyl group,
-CH2CH3,
-C(O)CH3,
-CH2CH2OH,
-CH2CH2CH3,
-CH2CH2OCH3,
-CH2CH(OH)CH3,
-CH2C(O)OCH3,
-C(O)CH(CH3)2,
-CH2CH2N(CH3)2,
-CH2CH2CH2N(CH3)2,
-OCH2CH2NH2,
-NH2,
-NHCH3,
-N(CH3)2,
-NHC(O)-CNH2(CH3)2,
-NHC(O)CH2NH2,
-NHC(O)CHCH3NH2,
-NHC(O)-CNH2(CH3)2,
- NHC (O) amino tetrahydro pyran base,
-CH2NH2,
-CH2CH2NH2,
-CH2CH2CH2NH2,
-CH2N(CH3)2,
- C (O) amino oxetanyl,
-S(O)2CH2CH3,
-S(O)2CH3,
Benzoyl,
3- pyrrolidinylpropyl,
Cvclopropvlmethvl,
Piperidyl,
Morpholinyl,
Morpholinyl methyl,
Methyl piperazine ylmethyl,
Pyrrolidinyl,
Pyrrolidinylmethyl,
Piperizinylmethyl,
Oxoimidazolidinyl, and
2- hydroxyethylpiperidine base；
On condition that:
R71And R77It is not all hydrogen；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, in formula (VII) compound, R72And R73It is not hydrogen.
The present invention relates to the purposes of new formula (VIIaar) compound and formula (VIIaar) compound in the methods of the invention:
Wherein:
Y7aarIt is selected from: S and NH；
R70aarIt is selected from:
Ethyl,
-CH2CF3,
-NCH3,
-SCH3,
Ethyoxyl,
Methoxyl group,
Phenyl,
Furyl, and
Cyclopropyl；
R71aarIt is selected from:
Hydrogen,
-C(O)NH2,
Heterocyclylalkyl, and
By oxo ,-C (O) CH3Or-NHC (O) CH3Substituted Heterocyclylalkyl；
R77aarIt is selected from:
Hydrogen,
C1-3Alkyl, and
Aryl,
The aryl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
C1-6Alkyl,
The C replaced by 1-3 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-CN ,-OR79a With-NR76aR77a,
Wherein R76aAnd R77aIndependently selected from: hydrogen ,-S (O)2CH3、C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR78aR79aReplace 1-6-OC1-5 Alkyl, wherein R78aAnd R79aIndependently selected from: hydrogen, phenyl, C1-5It alkyl and is taken by 1-4 substituent groups independently selected from the following The C in generation1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
- CN,
S(O)2NH2, and
-S(O)2NHCH3,
Pyridyl group,
Thiazolyl, and
By-C (O) CH3Or-NHC (O) CH3Substituted thiazolyl；
R72aarAnd R73aarIndependently selected from:
Hydrogen,
C1-3Alkyl,
The C replaced by 1-3 substituent groups independently selected from the following1-3Alkyl :-OH, oxo ,-NH2, morpholino and methoxy Base,
5- oxa- -2- azaspiro [3.4] octyl, and
8- azabicyclo [3.2.1] octyl, or
R72aarAnd R73aarNitrogen connected to them and optional 1-3 additional hetero atoms are formed together Heterocyclylalkyl, It is selected from:
Pyrrolidinyl,
Piperidyl,
Isosorbide-5-Nitrae-Diazesuberane base,
Piperazinyl,
2,9- diaza spiros [5.5] undecyl,
2,8- diaza spiros [4.5] decyl,
Hexahydro -1H- pyrrolo- [1,2a] [Isosorbide-5-Nitrae] diaza cycloheptatriene base,
Morpholinyl,
1- oxa- -6- azaspiro [3.4] octyl,
1,7- diaza spiro [3.5] nonyl,
2,7- diaza spiros [3.5] nonyl,
2,6- diaza spiros [3.4] octyl,
Azetidinyl,
1,8- diaza spiro [4.5] decyl, and
5- oxa- -2- azaspiro [3.4] octyl,
All of which is optionally replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Oxo,
- OH,
-CH3,
-CH2OH,
Methoxyl group,
-CH2CH3,
-C(O)CH3,
-CH2CH2OH,
-CH2CH2CH3,
-CH2CH2OCH3,
-CH2CH(OH)CH3,
-CH2C(O)OCH3,
-C(O)CH(CH3)2,
-CH2CH2N(CH3)2,
-CH2CH2CH2N(CH3)2,
-OCH2CH2NH2,
-OCH2CH2OH,
-NH2,
-NHCH3,
-N(CH3)2,
-NHC(O)-CNH2(CH3)2,
-NHC(O)CH2NH2,
-NHC(O)CHCH3NH2,
-NHC(O)-CNH2(CH3)2,
- NHC (O) amino tetrahydro pyran base,
-CH2NH2,
-CH2CH2NH2,
-CH2CH2CH2NH2,
-CH2N(CH3)2,
- C (O) amino oxetanyl,
- C (O) amino tetrahydro pyran base,
-S(O)2CH2CH3,
-S(O)2CH3,
Benzoyl,
3- pyrrolidinylpropyl,
Cvclopropvlmethvl,
Piperidyl,
Morpholinyl,
Morpholinyl methyl,
Methyl piperazine ylmethyl,
Methyl piperazine base,
Pyrrolidinyl,
Pyrrolidinylmethyl,
Piperizinylmethyl,
Oxoimidazolidinyl, and
2- hydroxyethylpiperidine base；
On condition that:
R72aarAnd R73aarNot all be hydrogen and
R71aarAnd R77aarIt is not all hydrogen；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, in formula (VIIaar) compound, R72aarAnd R73aarIt is not hydrogen.
Suitably, in formula (VIIaar) compound, R71aarFor-C (O) NH2。
Suitably, in formula (VIIaar) compound, R77aarFor what is replaced by 1-4 substituent groups independently selected from the following Aryl:
Fluorine,
Chlorine,
C1-6Alkyl,
The C replaced by 1-3 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-CN ,-OR79a With-NR76aR77a,
Wherein R76aAnd R77aIndependently selected from: hydrogen ,-S (O)2CH3、C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR78aR79aReplace 1-6-OC1-5 Alkyl, wherein R78aAnd R79aIndependently selected from: hydrogen, phenyl, C1-5It alkyl and is taken by 1-4 substituent groups independently selected from the following The C in generation1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl.
The present invention relates to the purposes of new formula (VIIa) compound and formula (VIIa) compound in the methods of the invention:
Wherein:
Y7aIt is selected from: S and NH；
R70aIt is selected from:
Ethyl,
-CH2CF3,
-NCH3,
-SCH3,
Ethyoxyl, and
Cyclopropyl；
R71aIt is selected from:
Hydrogen,
-C(O)NH2,
Heterocyclylalkyl, and
By oxo ,-C (O) CH3Or-NHC (O) CH3Substituted Heterocyclylalkyl；
R77aIt is selected from:
Hydrogen,
C1-3Alkyl, and
Aryl,
The aryl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
C1-6Alkyl,
The C replaced by 1-3 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-CN ,-OR79a With-NR76aR77a,
Wherein R76aAnd R77aIndependently selected from: hydrogen ,-S (O)2CH3、C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR78aR79aReplace 1-6-OC1-5 Alkyl, wherein R78aAnd R79aIndependently selected from: hydrogen, phenyl, C1-5It alkyl and is taken by 1-4 substituent groups independently selected from the following The C in generation1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
- CN,
S(O)2NH2, and
-S(O)2NHCH3,
Pyridyl group,
Thiazolyl, and
By-C (O) CH3Or-NHC (O) CH3Substituted thiazolyl；
R72aAnd R73aIndependently selected from:
Hydrogen,
C1-3Alkyl,
The C replaced by 1-3 substituent groups independently selected from the following1-3Alkyl :-OH, oxo ,-NH2, morpholino and methoxy Base,
5- oxa- -2- azaspiro [3.4] octyl, and
8- azabicyclo [3.2.1] octyl, or
R72aAnd R73aNitrogen connected to them and optional 1-3 additional hetero atoms these Heterocyclylalkyls together, It is selected from:
Pyrrolidinyl,
Piperidyl,
Isosorbide-5-Nitrae-Diazesuberane base,
Piperazinyl,
2,9- diaza spiros [5.5] undecyl,
2,8- diaza spiros [4.5] decyl,
Hexahydro -1H- pyrrolo- [1,2a] [Isosorbide-5-Nitrae] diaza cycloheptatriene base,
Morpholinyl,
1- oxa- -6- azaspiro [3.4] octyl,
1,7- diaza spiro [3.5] nonyl,
2,7- diaza spiros [3.5] nonyl,
2,6- diaza spiros [3.4] octyl,
Azetidinyl,
1,8- diaza spiro [4.5] decyl, and
5- oxa- -2- azaspiro [3.4] octyl,
All of which is optionally replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Oxo,
- OH,
-CH3,
-CH2OH,
Methoxyl group,
-CH2CH3,
-C(O)CH3,
-CH2CH2OH,
-CH2CH2CH3,
-CH2CH2OCH3,
-CH2CH(OH)CH3,
-CH2C(O)OCH3,
-C(O)CH(CH3)2,
-CH2CH2N(CH3)2,
-CH2CH2CH2N(CH3)2,
-OCH2CH2NH2,
-NH2,
-NHCH3,
-N(CH3)2,
-NHC(O)-CNH2(CH3)2,
-NHC(O)CH2NH2,
-NHC(O)CHCH3NH2,
-NHC(O)-CNH2(CH3)2,
- NHC (O) amino tetrahydro pyran base,
-CH2NH2,
-CH2CH2NH2,
-CH2CH2CH2NH2,
-CH2N(CH3)2,
- C (O) amino oxetanyl,
-S(O)2CH2CH3,
-S(O)2CH3,
Benzoyl,
3- pyrrolidinylpropyl,
Cvclopropvlmethvl,
Piperidyl,
Morpholinyl,
Morpholinyl methyl,
Methyl piperazine ylmethyl,
Pyrrolidinyl,
Pyrrolidinylmethyl,
Piperizinylmethyl,
Oxoimidazolidinyl, and
2- hydroxyethylpiperidine base；
On condition that:
R72aAnd R73aNot all be hydrogen and
R71aAnd R77aIt is not all hydrogen；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, in formula (VIIa) compound, R72aAnd R73aIt is not hydrogen.
Included in the compounds of this invention and it is used in the method for the present invention be formula (VIII) compound:
Wherein:
Y8It is selected from: S and NH；
R80It is selected from:
Ethyl,
-CH2CF3,
-NCH3,
-SCH3,
Ethyoxyl, and
Cyclopropyl；
R81It is selected from:
Hydrogen,
-C(O)NH2,
Heterocyclylalkyl, and
By oxo ,-C (O) CH3Or-NHC (O) CH3Substituted Heterocyclylalkyl；
R87It is selected from:
Hydrogen,
CH3,
Phenyl,
The phenyl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
C1-6Alkyl,
The C replaced by 1-3 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-CN ,-OR89 With-NR86R87,
Wherein R86And R87Independently selected from: hydrogen ,-S (O)2CH3、C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR88R89Replace 1-6-OC1-5Alkane Base, wherein R88And R89Independently selected from: hydrogen, phenyl, C1-5Alkyl and replaced by 1-4 substituent groups independently selected from the following C1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
- CN,
S(O)2NH2, and
-S(O)2NHCH3,
Pyridyl group,
Thiazolyl, and
By-C (O) CH3Or-NHC (O) CH3Substituted thiazolyl；
R82And R83Independently selected from:
Hydrogen,
C1-3Alkyl,
The C replaced by 1-3 substituent groups independently selected from the following1-3Alkyl :-OH, oxo ,-NH2, morpholino and methoxy Base,
5- oxa- -2- azaspiro [3.4] octyl, and
8- azabicyclo [3.2.1] octyl, or
R82And R83Nitrogen connected to them and optional 1-3 additional hetero atoms are formed together Heterocyclylalkyl, select From:
Pyrrolidinyl,
Piperidyl,
Isosorbide-5-Nitrae-Diazesuberane base,
Piperazinyl,
2,9- diaza spiros [5.5] undecyl,
2,8- diaza spiros [4.5] decyl,
Hexahydro -1H- pyrrolo- [1,2a] [Isosorbide-5-Nitrae] diaza cycloheptatriene base,
Morpholinyl,
1- oxa- -6- azaspiro [3.4] octyl,
1,7- diaza spiro [3.5] nonyl,
2,7- diaza spiros [3.5] nonyl,
2,6- diaza spiros [3.4] octyl,
Azetidinyl,
1,8- diaza spiro [4.5] decyl, and
5- oxa- -2- azaspiro [3.4] octyl,
All of which is optionally replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Oxo,
- OH,
-CH3,
-CH2OH,
Methoxyl group,
-CH2CH3,
-C(O)CH3,
-CH2CH2OH,
-CH2CH2CH3,
-CH2CH2OCH3,
-CH2CH(OH)CH3,
-CH2C(O)OCH3,
-C(O)CH(CH3)2,
-CH2CH2N(CH3)2,
-CH2CH2CH2N(CH3)2,
-OCH2CH2NH2,
-NH2,
-NHCH3,
-N(CH3)2,
-NHC(O)-CNH2(CH3)2,
-NHC(O)CH2NH2,
-NHC(O)CHCH3NH2,
-NHC(O)-CNH2(CH3)2,
- NHC (O) amino tetrahydro pyran base,
-CH2NH2,
-CH2CH2NH2,
-CH2CH2CH2NH2,
-CH2N(CH3)2,
- C (O) amino oxetanyl,
-S(O)2CH2CH3,
-S(O)2CH3,
Benzoyl,
3- pyrrolidinylpropyl,
Cvclopropvlmethvl,
Piperidyl,
Morpholinyl,
Morpholinyl methyl,
Methyl piperazine ylmethyl,
Pyrrolidinyl,
Pyrrolidinylmethyl,
Piperizinylmethyl,
Oxoimidazolidinyl, and
2- hydroxyethylpiperidine base；
On condition that:
R81And R87It is not all hydrogen；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, in formula (VIII) compound, R82aAnd R83aIt is not hydrogen.
The present invention relates to the use of new formula (VIIIaar) compound and formula (VIIIaar) compound in the methods of the invention On the way:
Wherein:
Y8aarIt is selected from: S and NH；
R80aarIt is selected from:
Ethyl,
-CH2CF3,
-NCH3,
-SCH3,
Ethyoxyl,
Methoxyl group,
Phenyl,
Furyl, and
Cyclopropyl；
R81aarIt is selected from:
Hydrogen,
-C(O)NH2,
Heterocyclylalkyl, and
By oxo ,-C (O) CH3Or-NHC (O) CH3Substituted Heterocyclylalkyl；
R87aarIt is selected from:
Hydrogen,
CH3,
Phenyl,
The phenyl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
C1-6Alkyl,
The C replaced by 1-3 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-CN ,-OR89 With-NR86R87,
Wherein R86And R87Independently selected from: hydrogen ,-S (O)2CH3、C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR88R89Replace 1-6-OC1-5Alkane Base, wherein R88And R89Independently selected from: hydrogen, phenyl, C1-5Alkyl and replaced by 1-4 substituent groups independently selected from the following C1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
- CN,
-S(O)2NH2, and
-S(O)2NHCH3,
Pyridyl group,
Thiazolyl, and
By-C (O) CH3Or-NHC (O) CH3Substituted thiazolyl；
R82aarAnd R83aarIndependently selected from:
Hydrogen,
C1-3Alkyl,
The C replaced by 1-3 substituent groups independently selected from the following1-3Alkyl :-OH, oxo ,-NH2, morpholino and methoxy Base,
5- oxa- -2- azaspiro [3.4] octyl, and
8- azabicyclo [3.2.1] octyl, or
R82aarAnd R83aarNitrogen connected to them and optional 1-3 additional hetero atoms are formed together Heterocyclylalkyl, It is selected from:
Pyrrolidinyl,
Piperidyl,
Isosorbide-5-Nitrae-Diazesuberane base,
Piperazinyl,
2,9- diaza spiros [5.5] undecyl,
2,8- diaza spiros [4.5] decyl,
Hexahydro -1H- pyrrolo- [1,2a] [Isosorbide-5-Nitrae] diaza cycloheptatriene base,
Morpholinyl,
1- oxa- -6- azaspiro [3.4] octyl,
1,7- diaza spiro [3.5] nonyl,
2,7- diaza spiros [3.5] nonyl,
2,6- diaza spiros [3.4] octyl,
Azetidinyl,
1,8- diaza spiro [4.5] decyl, and
5- oxa- -2- azaspiro [3.4] octyl,
All of which is optionally replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Oxo,
- OH,
-CH3,
-CH2OH,
Methoxyl group,
-CH2CH3,
-C(O)CH3,
-CH2CH2OH,
-CH2CH2CH3,
-CH2CH2OCH3,
-CH2CH(OH)CH3,
-CH2C(O)OCH3,
-C(O)CH(CH3)2,
-CH2CH2N(CH3)2,
-CH2CH2CH2N(CH3)2,
-OCH2CH2NH2,
-OCH2CH2OH,
-NH2,
-NHCH3,
-N(CH3)2,
-NHC(O)-CNH2(CH3)2,
-NHC(O)CH2NH2,
-NHC(O)CHCH3NH2,
-NHC(O)-CNH2(CH3)2,
- NHC (O) amino tetrahydro pyran base,
-CH2NH2,
-CH2CH2NH2,
-CH2CH2CH2NH2,
-CH2N(CH3)2,
- C (O) amino oxetanyl,
- C (O) amino tetrahydro pyran base,
-S(O)2CH2CH3,
-S(O)2CH3,
Benzoyl,
3- pyrrolidinylpropyl,
Cvclopropvlmethvl,
Piperidyl,
Morpholinyl,
Morpholinyl methyl,
Methyl piperazine ylmethyl,
Methyl piperazine base,
Pyrrolidinyl,
Pyrrolidinylmethyl,
Piperizinylmethyl,
Oxoimidazolidinyl, and
2- hydroxyethylpiperidine base；
On condition that:
R81aarAnd R87aarIt is not all hydrogen, and
R82aarAnd R83aarIt is not all hydrogen；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, in formula (VIIIaar) compound, R82aarAnd R83aarIt is not hydrogen.
Suitably, in formula (VIIIaar) compound, R81aarFor-C (O) NH2。
Suitably, in formula (VIIIaar) compound, R87aarTo be replaced by 1-4 substituent groups independently selected from the following Phenyl:
Fluorine,
Chlorine,
C1-6Alkyl,
The C replaced by 1-3 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-CN ,-OR89 With-NR86R87,
Wherein R86And R87Independently selected from: hydrogen ,-S (O)2CH3、C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR88R89Replace 1-6-OC1-5Alkane Base, wherein R88And R89Independently selected from: hydrogen, phenyl, C1-5Alkyl and replaced by 1-4 substituent groups independently selected from the following C1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl.
The present invention relates to the purposes of new formula (VIIIa) compound and formula (VIIIa) compound in the methods of the invention:
Wherein:
Y8aIt is selected from: S and NH；
R80aIt is selected from:
Ethyl,
-CH2CF3,
-NCH3,
-SCH3,
Ethyoxyl, and
Cyclopropyl；
R81aIt is selected from:
Hydrogen,
-C(O)NH2,
Heterocyclylalkyl, and
By oxo ,-C (O) CH3Or-NHC (O) CH3Substituted Heterocyclylalkyl；
R87aIt is selected from:
Hydrogen,
CH3,
Phenyl,
The phenyl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
C1-6Alkyl,
The C replaced by 1-3 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-CN ,-OR89 With-NR86R87,
Wherein R86And R87Independently selected from: hydrogen ,-S (O)2CH3、C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR88R89Replace 1-6-OC1-5Alkane Base, wherein R88And R89Independently selected from: hydrogen, phenyl, C1-5Alkyl and replaced by 1-4 substituent groups independently selected from the following C1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
- CN,
-S(O)2NH2, and
-S(O)2NHCH3,
Pyridyl group,
Thiazolyl, and
By-C (O) CH3Or-NHC (O) CH3Substituted thiazolyl；
R82aAnd R83aIndependently selected from:
Hydrogen,
C1-3Alkyl,
The C replaced by 1-3 substituent groups independently selected from the following1-3Alkyl :-OH, oxo ,-NH2, morpholino and methoxy Base,
5- oxa- -2- azaspiro [3.4] octyl, and
8- azabicyclo [3.2.1] octyl, or
R82aAnd R83aNitrogen connected to them and optional 1-3 additional hetero atoms are formed together Heterocyclylalkyl, It is selected from:
Pyrrolidinyl,
Piperidyl,
Isosorbide-5-Nitrae-Diazesuberane base,
Piperazinyl,
2,9- diaza spiros [5.5] undecyl,
2,8- diaza spiros [4.5] decyl,
Hexahydro -1H- pyrrolo- [1,2a] [Isosorbide-5-Nitrae] diaza cycloheptatriene base,
Morpholinyl,
1- oxa- -6- azaspiro [3.4] octyl,
1,7- diaza spiro [3.5] nonyl,
2,7- diaza spiros [3.5] nonyl,
2,6- diaza spiros [3.4] octyl,
Azetidinyl,
1,8- diaza spiro [4.5] decyl, and
5- oxa- -2- azaspiro [3.4] octyl,
All of which is optionally replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Oxo,
- OH,
-CH3,
-CH2OH,
Methoxyl group,
-CH2CH3,
-C(O)CH3,
-CH2CH2OH,
-CH2CH2CH3,
-CH2CH2OCH3,
-CH2CH(OH)CH3,
-CH2C(O)OCH3,
-C(O)CH(CH3)2,
-CH2CH2N(CH3)2,
-CH2CH2CH2N(CH3)2,
-OCH2CH2NH2,
-NH2,
-NHCH3,
-N(CH3)2,
-NHC(O)-CNH2(CH3)2,
-NHC(O)CH2NH2,
-NHC(O)CHCH3NH2,
-NHC(O)-CNH2(CH3)2,
- NHC (O) amino tetrahydro pyran base,
-CH2NH2,
-CH2CH2NH2,
-CH2CH2CH2NH2,
-CH2N(CH3)2,
- C (O) amino oxetanyl,
-S(O)2CH2CH3,
-S(O)2CH3,
Benzoyl,
3- pyrrolidinylpropyl,
Cvclopropvlmethvl,
Piperidyl,
Morpholinyl,
Morpholinyl methyl,
Methyl piperazine ylmethyl,
Pyrrolidinyl,
Pyrrolidinylmethyl,
Piperizinylmethyl,
Oxoimidazolidinyl, and
2- hydroxyethylpiperidine base；
On condition that:
R81aAnd R87aIt is not all hydrogen, and
R82aAnd R83aIt is not all hydrogen；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, in formula (VIIIa) compound, R82aAnd R83aIt is not hydrogen.
The present invention relates to the purposes of new formula (Q) compound and formula (Q) compound in the methods of the invention:
Wherein:
Y7a’It is selected from: S and NH；
R70a’It is selected from:
Ethyl,
-CH2CF3, and
Cyclopropyl；
R71a’It is selected from:
Hydrogen,
CH3,
Phenyl,
The phenyl that is replaced by chlorine and
Pyridine,
R77a’It is selected from:
-C(O)NH2With
Aryl,
The aryl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
C1-6Alkyl,
The C replaced by 1-3 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-CN ,- OR79a’With-NR76a’R77a’,
Wherein R76a’And R77a’Independently selected from: hydrogen ,-S (O)2CH3、C1-5Alkyl and independently selected from the following by 1-4 The C that substituent group replaces1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR78a’R79a’Substitution 1-6 times- OC1-5Alkyl, wherein R78a’And R79a’Independently selected from: hydrogen, phenyl, C1-5Alkyl and by 1-4 substitutions independently selected from the following The C that base replaces1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
-S(O)2NH2,
-S(O)2NHCH3, and
R72a’And R73a’Independently selected from:
Hydrogen,
C1-3Alkyl,
The C replaced by 1-3 substituent groups independently selected from the following1-3Alkyl: morpholino and methoxyl group,
5- oxa- -2- azaspiro [3.4] octyl, and
8- azabicyclo [3.2.1] octyl, or
R72a’And R73a’Nitrogen connected to them and optional 1-3 additional hetero atoms are formed together Heterocyclylalkyl, It is selected from:
Pyrrolidinyl,
Piperidyl,
Isosorbide-5-Nitrae-Diazesuberane base,
Piperazinyl,
2,9- diaza spiros [5.5] undecyl,
2,8- diaza spiros [4.5] decyl,
Octahydro -1H- pyrrolo- [1,2a] [Isosorbide-5-Nitrae] diaza cycloheptatriene base,
Morpholinyl,
1- oxa- -6- azaspiro [3.4] octyl,
1,7- diaza spiro [3.5] nonyl,
2,7- diaza spiros [3.5] nonyl,
2,6- diaza spiros [3.4] octyl,
Azetidinyl,
1,8- diaza spiro [4.5] decyl, and
5- oxa- -2- azaspiro [3.4] octyl,
All of which is optionally replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Oxo,
- OH,
-CH3,
-CH2OH,
Methoxyl group,
-CH2CH3,
-C(O)CH3,
-CH2CH2OH,
-CH2CH2CH3,
-CH2CH2OCH3,
-CH2CH(OH)CH3,
-CH2C(O)OCH3,
-C(O)CH(CH3)2,
-CH2CH2N(CH3)2,
-CH2CH2CH2N(CH3)2,
-NH2,
-NHCH3,
-N(CH3)2,
-CH2NH2,
-CH2CH2NH2,
-CH2CH2CH2NH2,
-CH2N(CH3)2,
-S(O)2CH2CH3,
-S(O)2CH3,
Benzoyl,
3- pyrrolidinylpropyl,
2- Cvclopropvlmethvl,
Piperidyl,
Morpholinyl,
Morpholinyl methyl,
Methyl piperazine ylmethyl,
Pyrrolidinyl,
Pyrrolidinylmethyl,
Piperizinylmethyl,
Oxoimidazolidinyl, and
2- hydroxyethylpiperidine base；
On condition that:
R72a’And R73a’It is not all hydrogen；
Or its pharmaceutically acceptable salt.
Suitably, in formula (Q) compound, R72a’And R73a’It is not hydrogen.
The present invention relates to the purposes of new formula (T) compound and formula (T) compound in the methods of the invention:
Wherein:
R80It is selected from:
Ethyl,
-CH2CF3, and
Cyclopropyl；
R81It is selected from:
Phenyl, and
By chlorine or fluorine-substituted phenyl and
R72a’And R73a’Independently selected from:
C1-3Alkyl,
The C replaced by 1-3 substituent groups independently selected from the following1-3Alkyl: oxo and NH2, or
R72a’And R73a’Nitrogen connected to them and optional 1-3 additional hetero atoms are formed together Heterocyclylalkyl, It is selected from:
Pyrrolidinyl,
Piperidyl,
Isosorbide-5-Nitrae-Diazesuberane base,
Piperazinyl,
2,9- diaza spiros [5.5] undecyl,
2,8- diaza spiros [4.5] decyl,
Octahydro -1H- pyrrolo- [1,2a] [Isosorbide-5-Nitrae] diaza cycloheptatriene base,
Morpholinyl,
1- oxa- -6- azaspiro [3.4] octyl,
1,7- diaza spiro [3.5] nonyl,
2,7- diaza spiros [3.5] nonyl,
2,6- diaza spiros [3.4] octyl,
Azetidinyl,
1,8- diaza spiro [4.5] decyl, and
5- oxa- -2- azaspiro [3.4] octyl,
All of which is optionally replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Oxo,
- OH,
-CH3,
-CH2OH,
Methoxyl group,
-CH2CH3,
-C(O)CH3,
-CH2CH2OH,
-CH2CH2CH3,
-CH2CH2OCH3,
-CH2CH(OH)CH3,
-CH2C(O)OCH3,
-C(O)CH(CH3)2,
-CH2CH2N(CH3)2,
-CH2CH2CH2N(CH3)2,
-NH2,
-NHCH3,
-N(CH3)2,
-NHCH2C(CH3)3,
-N(CH3) cyclobutane base,
-CH2NH2,
-CH2CH2NH2,
-CH2CH2CH2NH2,
-CH2N(CH3)2,
-S(O)2CH2CH3,
-S(O)2CH3,
Benzoyl,
3- pyrrolidinylpropyl,
2- Cvclopropvlmethvl,
Piperidyl,
Morpholinyl,
Morpholinyl methyl,
Methyl piperazine ylmethyl,
Pyrrolidinyl,
Pyrrolidinylmethyl,
Piperizinylmethyl,
Oxoimidazolidinyl, and
2- hydroxyethylpiperidine base；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, in formula (T) compound, the compound is the form of phosphate prodrugs.
The present invention relates to the purposes of new formula (Ta) compound and formula (Ta) compound in the methods of the invention:
Wherein:
R80aIt is selected from:
Ethyl,
-CH2CF3, and
Cyclopropyl；
R81aIt is selected from:
Phenyl, and
By chlorine and fluorine-substituted phenyl and
R82aAnd R83aNitrogen connected to them and optional 1-3 additional hetero atoms are formed together Heterocyclylalkyl, It is selected from:
Pyrrolidinyl,
Piperidyl,
Isosorbide-5-Nitrae-Diazesuberane base,
Piperazinyl,
2,9- diaza spiros [5.5] undecyl,
2,8- diaza spiros [4.5] decyl,
Octahydro -1H- pyrrolo- [1,2a] [Isosorbide-5-Nitrae] diaza cycloheptatriene base,
Morpholinyl,
1- oxa- -6- azaspiro [3.4] octyl,
1,7- diaza spiro [3.5] nonyl,
2,7- diaza spiros [3.5] nonyl,
2,6- diaza spiros [3.4] octyl,
Azetidinyl,
1,8- diaza spiro [4.5] decyl, and
5- oxa- -2- azaspiro [3.4] octyl,
All of which is optionally replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Oxo,
- OH,
-CH3,
-CH2OH,
Methoxyl group,
-CH2CH3,
-C(O)CH3,
-CH2CH2OH,
-CH2CH2CH3,
-CH2CH2OCH3,
-CH2CH(OH)CH3,
-CH2C(O)OCH3,
-C(O)CH(CH3)2,
-CH2CH2N(CH3)2,
-CH2CH2CH2N(CH3)2,
-NH2,
-NHCH3,
-N(CH3)2,
-NHCH2C(CH3)3,
-N(CH3) cyclobutane base,
-CH2NH2,
-CH2CH2NH2,
-CH2CH2CH2NH2,
-CH2N(CH3)2,
-S(O)2CH2CH3,
-S(O)2CH3,
Benzoyl,
3- pyrrolidinylpropyl,
2- Cvclopropvlmethvl,
Piperidyl,
Morpholinyl,
Morpholinyl methyl,
Methyl piperazine ylmethyl,
Pyrrolidinyl,
Pyrrolidinylmethyl,
Piperizinylmethyl,
Oxoimidazolidinyl, and
2- hydroxyethylpiperidine base；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, in formula (Ta) compound, the compound is the form of phosphate prodrugs.
The present invention relates to the purposes of new formula (S) compound and formula (S) compound in the methods of the invention:
Wherein:
R90It is selected from:
Ethyl,
-CH2CF3, and
Cyclopropyl；
R91It is selected from:
Phenyl, and
The phenyl replaced by 1-2 substituent groups independently selected from the following:
Fluorine,
Chlorine,
C1-4Alkoxy,
The C replaced by 1-3 substituent groups independently selected from the following1-4Alkoxy: fluorine, chlorine, oxo ,-OH ,-NH2、- NHCH3With-N (CH3)2,
C1-6Alkyl,
The C replaced by 1-3 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-S (O)2CH3、-CN、-OR79a’With-NR76a’R77a’,
Wherein R76a’And R77a’Independently selected from: hydrogen ,-S (O)2CH3、C1-5Alkyl and independently selected from the following by 1-4 The C that substituent group replaces1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR78a’R79a’Substitution 1-6 times- OC1-5Alkyl, wherein R78a’And R79a’Independently selected from: hydrogen, phenyl, C1-5Alkyl and by 1-4 substitutions independently selected from the following The C that base replaces1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
Tetrahydro isothiazolyl,
Tetrahydro isothiazolyl twice is replaced by oxo,
Tetrahydro -1,2-thiazines base,
Tetrahydro twice -1,2-thiazines base is replaced by oxo,
-N(CH3)S(O)2CH3,
-N(CH3)S(O)2CFH2,
-N(CH3)S(O)2CF2H,
-N(CH3)S(O)2CF3,
-OS(O)2CH3,
-S(O)2NH2With
-S(O)2NHCH3, and
R92And R93Independently selected from:
C1-3Alkyl,
The C replaced by 1-3 substituent groups independently selected from the following1-3Alkyl: oxo,
-N(CH2CH3)3、-CH2CH2Piperidyl and NH2, or
R92And R93Nitrogen connected to them and optional 1-3 additional hetero atoms are formed together Heterocyclylalkyl, select From:
Pyrrolidinyl,
Piperidyl,
Isosorbide-5-Nitrae-Diazesuberane base,
Piperazinyl,
2,9- diaza spiros [5.5] undecyl,
2,8- diaza spiros [4.5] decyl,
Octahydro -1H- pyrrolo- [1,2a] [Isosorbide-5-Nitrae] diaza cycloheptatriene base,
Morpholinyl,
1- oxa- -6- azaspiro [3.4] octyl,
1,7- diaza spiro [3.5] nonyl,
2,7- diaza spiros [3.5] nonyl,
2,6- diaza spiros [3.4] octyl,
Azetidinyl,
1,8- diaza spiro [4.5] decyl, and
5- oxa- -2- azaspiro [3.4] octyl,
All of which is optionally replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Oxo,
- OH,
-CH3,
-CH2OH,
Methoxyl group,
-CH2CH3,
-C(O)CH3,
-CH2CH2OH,
-CH2CH2CH3,
-CH2CH2OCH3,
-CH2CH(OH)CH3,
-CH2C(O)OCH3,
-C(O)CH(CH3)2,
-CH2CH2N(CH3)2,
-CH2N(CH3)2,
-CH2CH2CH2N(CH3)2,
-NH2,
-NHCH3,
-N(CH3)2,
-NHCH2C(CH3)3,
-NHCH(CH3)2,
-NHC(O)CH(CH3)(NH2),
-NHC(O)C(CH3)3,
-N(CH3) cyclobutane base,
-CH2NH2,
-CH2Pyrrolidinyl,
-CH2CH2NH2,
-CH2CH2CH2NH2,
-CH2N(CH3)2,
-S(O)2CH2CH3,
-S(O)2CH3,
Benzoyl,
3- pyrrolidinylpropyl,
2- Cvclopropvlmethvl,
Piperidyl,
Morpholinyl,
Morpholinyl methyl,
Methyl piperazine ylmethyl,
Pyrrolidinyl,
Pyrrolidinylmethyl,
Piperizinylmethyl,
Oxoimidazolidinyl, and
2- hydroxyethylpiperidine base；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, in formula (S) compound, the compound is the form of phosphate prodrugs.
The present invention relates to the purposes of new formula (Sa) compound and formula (Sa) compound in the methods of the invention:
Wherein:
R90aIt is selected from:
Ethyl,
-CH2CF3, and
Cyclopropyl；
R91aIt is selected from:
Phenyl, and
The phenyl replaced by 1-2 substituent groups independently selected from the following:
Fluorine,
Chlorine,
C1-4Alkoxy,
The C replaced by 1-3 substituent groups independently selected from the following1-4Alkoxy: fluorine, chlorine, oxo ,-OH ,-NH2、- NHCH3With-N (CH3)2,
C1-6Alkyl,
The C replaced by 1-3 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-S (O)2CH3、-CN、-OR79a’With-NR76a’R77a’,
Wherein R76a’And R77a’Independently selected from: hydrogen ,-S (O)2CH3、C1-5Alkyl and independently selected from the following by 1-4 The C that substituent group replaces1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR78a’R79a’Substitution 1-6 times- OC1-5Alkyl, wherein R78a’And R79a’Independently selected from: hydrogen, phenyl, C1-5Alkyl and by 1-4 substitutions independently selected from the following The C that base replaces1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
Tetrahydro isothiazolyl,
Tetrahydro isothiazolyl twice is replaced by oxo,
Tetrahydro -1,2-thiazines base,
Tetrahydro twice -1,2-thiazines base is replaced by oxo,
-N(CH3)S(O)2CH3,
-N(CH3)S(O)2CFH2,
-N(CH3)S(O)2CF2H,
-N(CH3)S(O)2CF3,
-OS(O)2CH3,
-S(O)2NH2With
-S(O)2NHCH3, and
R92aAnd R93aIndependently selected from:
C1-3Alkyl,
The C replaced by 1-3 substituent groups independently selected from the following1-3Alkyl: oxo ,-N (CH2CH3)3、-CH2CH2Piperidines Base and NH2, or
R92aAnd R93aNitrogen connected to them and optional 1-3 additional hetero atoms are formed together Heterocyclylalkyl, It is selected from:
Pyrrolidinyl,
Piperidyl,
Isosorbide-5-Nitrae-Diazesuberane base,
Piperazinyl,
2,9- diaza spiros [5.5] undecyl,
2,8- diaza spiros [4.5] decyl,
Octahydro -1H- pyrrolo- [1,2a] [Isosorbide-5-Nitrae] diaza cycloheptatriene base,
Morpholinyl,
1- oxa- -6- azaspiro [3.4] octyl,
1,7- diaza spiro [3.5] nonyl,
2,7- diaza spiros [3.5] nonyl,
2,6- diaza spiros [3.4] octyl,
Azetidinyl,
1,8- diaza spiro [4.5] decyl, and
5- oxa- -2- azaspiro [3.4] octyl,
All of which is optionally replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Oxo,
- OH,
-CH3,
-CH2OH,
Methoxyl group,
-CH2CH3,
-C(O)CH3,
-CH2CH2OH,
-CH2CH2CH3,
-CH2CH2OCH3,
-CH2CH(OH)CH3,
-CH2C(O)OCH3,
-C(O)CH(CH3)2,
-CH2CH2N(CH3)2,
-CH2N(CH3)2,
-CH2CH2CH2N(CH3)2,
-NH2,
-NHCH3,
-N(CH3)2,
-NHCH2C(CH3)3,
-NHCH(CH3)2,
-NHC(O)CH(CH3)(NH2),
-NHC(O)C(CH3)3,
-N(CH3) cyclobutane base,
-CH2NH2,
-CH2Pyrrolidinyl,
-CH2CH2NH2,
-CH2CH2CH2NH2,
-CH2N(CH3)2,
-S(O)2CH2CH3,
-S(O)2CH3,
Benzoyl,
3- pyrrolidinylpropyl,
2- Cvclopropvlmethvl,
Piperidyl,
Morpholinyl,
Morpholinyl methyl,
Methyl piperazine ylmethyl,
Pyrrolidinyl,
Pyrrolidinylmethyl,
Piperizinylmethyl,
Oxoimidazolidinyl, and
2- hydroxyethylpiperidine base；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, in formula (Sa) compound, the compound is the form of phosphate prodrugs.
Primary amide
The present invention relates to the purposes of formula (Ibr) compound and formula (Ibr) compound in the methods of the invention:
Wherein:
X1brAnd X2brIndependently selected from:
Hydrogen,
- CN,
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
Re,
-OC1-6Alkyl,
-ORe,
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl,
By RdReplace 1-4 Heterocyclylalkyl,
- SH, and
-SRa；
YbrIt is selected from: S, NH, NRz, O, S (O) and S (O)2；
R1brIt is selected from:
-NH2,
-NHRa,
-NRbRc,
- CN,
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
Re,
-OC1-6Alkyl,
-ORe,
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl,
By RdReplace 1-4 Heterocyclylalkyl,
Aryl,
By RdReplace 1-4 aryl,
Heteroaryl,
By RdReplace 1-4 heteroaryl,
- SH, and
-SRa；
R3brIt is selected from:
Hydrogen,
C1-6Alkyl,
Re,
Heterocyclylalkyl,
By RdReplace 1-4 Heterocyclylalkyl,
Aryl,
By RdReplace 1-4 aryl,
Heteroaryl, and
By RdReplace 1-4 heteroaryl；With
R5brIt is selected from:
-NH2,
-NHRa,
-NRbRc,
Aryl,
By RdReplace 1-4 aryl,
-C1-6Alkyl,
-OC1-6Alkyl,
-ORe,
- O aryl,
By RdReplace 1-4-O aryl,
- O heteroaryl,
By RdReplace 1-4-O heteroaryl,
- SH, and
-SRa；
Wherein:
Each RaIndependently selected from
C1-6Alkyl,
Re,
Aryl,
By RdReplace 1-4 aryl,
Heteroaryl,
By RdReplace 1-4 heteroaryl,
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl, and
By RdReplace 1-4 Heterocyclylalkyl；
RbAnd RcIndependently selected from:
C1-6Alkyl,
Re,
Aryl,
By RdReplace 1-4 aryl,
Heteroaryl,
By RdReplace 1-4 heteroaryl；
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl, and
By RdReplace 1-4 Heterocyclylalkyl, or
RbAnd RcNitrogen connected to them and the optional 1-3 additional hetero atoms independently selected from O, N and S are together Heterocyclylalkyl is formed, is optionally replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
Re,
-ORe,
Aryl,
By RdReplace 1-4 aryl,
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl, and
By RdReplace 1-4 Heterocyclylalkyl,
C1-4Alkoxy,
- CN,
Oxo,
- OH,
- COOH,
-NO2,
-NH2,
-N(H)C1-5Alkyl,
-N(H)Re,
-N(C1-5Alkyl)2,
-NReRe,
-N(Re)C1-5Alkyl,
-ONHC(NH)NH2,
- O Heterocyclylalkyl,
- NH naphthenic base,
-N(C1-5Alkyl) naphthenic base,
- NH Heterocyclylalkyl,
-N(C1-5Alkyl) Heterocyclylalkyl,
-S(O)2C1-4Alkyl,
-SO2NH2
-S(O)2Phenyl,
Benzoyl,
2- methylcyclopropyl groups,
Imidazole radicals,
(methoxypyridylmethyl) amino,
(methylcyclopropylmethyl) amino,
(fluorophenyl methyl) amino,
(methy oxetane ylmethyl) amino, and
(methyl-cyclobutyl methyl) amino,
Each RdIndependently selected from:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
Re,
Heteroaryl,
By RxReplace 1-4 heteroaryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Naphthenic base,
By RxReplace 1-4 naphthenic base,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Heterocyclylalkyl,
By RxReplace 1-4 Heterocyclylalkyl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Aryl,
By RxReplace 1-4 aryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
C1-4Alkoxy,
Replaced 1-4 C by fluorine1-4Alkoxy,
- O aryl,
By RxReplace 1-4-O aryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-ORe,
- C (O) H,
-C(O)Rzz,
- C (O) aryl,
By RzzFor 1-4-C (O) aryl,
- C (O) heteroaryl,
By RzzFor 1-4-C (O) heteroaryl,
- OC (O) H,
-CO(O)Rzz,
- OC (O) aryl,
By RzzFor 1-4-CO (O) aryl,
- OC (O) heteroaryl,
By RzzFor 1-4-OC (O) heteroaryl,
- SH,
-SRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- S (O) H,
-S(O)Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2H,
-S(O)2Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2NH2,
-S(O)2NHRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl, and by 1-6 The C that a substituent group independently selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-P(O)(CH3)2,
-NHS(O)2H,
-NHS(O)2Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- NHC (O) H,
-NHC(O)Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-C(O)NH2,
-C(O)NHRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-C(O)NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 The C that substituent group independently selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- C (O) OH,
-C(O)ORx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Oxo,
- OH,
-NH2,
-NHRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl, and by 1-6 The C that a substituent group independently selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-NH2,
- CN,
-NHC(O)NH2,
-NHC(O)NHRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-NHC(O)NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl, and by 1-6 The C that a substituent group independently selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Each ReIndependently selected from:
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Fluorine,
Chlorine,
Bromine,
Iodine,
-OC1-6Alkyl,
- the OC replaced by 1-6 substituent groups independently selected from the following1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2 With-CN,
-OC(O)C1-6Alkyl,
- OC (O) C replaced by 1-6 substituent groups independently selected from the following1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,- NH2With-CN,
-ONHC(NH)NH2,
-OP(O)(OH)2,
- SH,
-SRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- S (O) H,
-S(O)Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2H,
-S(O)2Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Oxo,
- OH,
-NH2,
-NHRxx,
Wherein RxxSelected from aryl, heteroaryl, naphthenic base, by C1-4The naphthenic base of alkoxy substitution is independently selected by 1-6 The C replaced from substituent group below1-4Alkoxy: fluorine, triazolyl, cyclopropyl, oxo ,-ORxy,-COOH ,-CN and-NRxyRxz,
Wherein RxyAnd RxzIndependently selected from: hydrogen, aryl, C1-5Alkyl cycloheteroalkyl, C1-6Alkyl and by 1-6 independently The C that substituent group selected from the following replaces1-6Alkyl: fluorine, oxo ,-ORxy,-COOH ,-CN and-NRxyRxz,
Wherein RxyAnd RxzIndependently selected from: hydrogen, aryl, C1-5Alkyl and by 1-4 substituent groups independently selected from the following Substituted C1-5Alkyl: fluorine, triazolyl, cyclopropyl, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5 Alkyl,
-NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-4Alkoxy, C1-6Alkane Base and the C replaced by 1-6 substituent groups independently selected from the following1-6Alkyl: fluorine, C1-4Alkoxy, triazolyl,
Cyclopropyl, oxo ,-OH ,-COOH ,-NH2With-CN, guanidine radicals,
- C (O) OH,
-C(O)ORx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-C(O)NH2,
-C(O)NHRx,
Wherein RxSelected from aryl, heteroaryl ,-OH, C1-4Alkoxy, naphthenic base, by HO- (C1-4Alkyl)-replace cycloalkanes Base, Heterocyclylalkyl, by HO- (C1-4Alkyl)-replace Heterocyclylalkyl, C1-6It alkyl and is taken by 1-6 is independently selected from the following The C replaced for base1-6Alkyl: fluorine, oxo ,-OH ,-COOH, heteroaryl ,-NH2With-CN,
-C(O)NRx1Rx2,
Wherein Rx1And Rx2Be each independently selected from aryl, heteroaryl, naphthenic base, by HO- (C1-4Alkyl)-replace cycloalkanes Base, Heterocyclylalkyl, C1-6Alkyl and the C1-6 alkyl replaced by 1-6 substituent groups independently selected from the following: fluorine, oxo ,- OH、-COOH、-NH2With-CN,
Or Rx1And Rx2Nitrogen connected to them and the optional 1-3 additional hetero atoms independently selected from O, N and S Be formed together Heterocyclylalkyl, optionally replaced by 1-5 substituent groups independently selected from the following: fluorine, oxo ,-OH,
HO-(C1-4Alkyl)-,-COOH ,-NH2With-CN, aryl,
By RxReplace 1-4 aryl,
Wherein RxSelected from fluorine, chlorine, bromine, iodine, aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 solely The on the spot C that substituent group selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2、-N(CH3)2、-NHC(O)C1-4Alkane Base and-CN,
- O aryl,
By RxReplace 1-4-O aryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2、-N(CH3)2With-CN,
Heteroaryl,
By RxReplace 1-4 heteroaryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-4Alkoxy, C1-6Alkyl and independent by 1-6 The C that ground substituent group selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN ,-O heteroaryl,
By RxReplace 1-4-O heteroaryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2、-N(CH3)2With-CN,
Naphthenic base,
By RxReplace 1-4 naphthenic base,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2,-N (CH3)2With-CN,
Heterocyclylalkyl,
By RxReplace 1-4 Heterocyclylalkyl,
Wherein RxSelected from oxo ,-OH ,-N (C1-4Alkyl)2, aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and The C replaced by 1-6 substituent groups independently selected from the following1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2、-N(CH3)2With- CN,
-S(O)2NH2,
-S(O)2NHRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 The C that substituent group independently selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN ,-NHS (O)2H,
-NHS(O)2Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-OC(O)NH2,
-NHC(O)Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-NHC(O)NHRxp,
Wherein RxpReplaced selected from heteroaryl, naphthenic base, Heterocyclylalkyl and by 1-4 substituent groups independently selected from the following C1-6Alkyl :-COOH ,-NH2With-CN,
-NHC(O)NRx3Rx4,
Wherein Rx3And Rx4Be each independently selected from heteroaryl, naphthenic base, Heterocyclylalkyl and by 1-6 independently selected from Under substituent group replace C1-6Alkyl :-COOH ,-NH2
With-CN,
-NHC(O)C(O)NH2,
-NO2With
-CN；With
RzIt is selected from
C1-6Alkyl,
Re,
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl, and
By RdReplace 1-4 Heterocyclylalkyl；
RzzIt is selected from
C1-6Alkyl, and
Re；
On condition that:
X1brAnd X2brIt is not all hydrogen；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, in formula (Ibr) compound, R3brFor optionally by RdReplace 1-4 aryl.
Suitably, in formula (Ibr) compound, X1brAnd X2brIt is not hydrogen.
Suitably, in formula (Ibr) compound, the compound is the form of phosphate prodrugs.
Suitably, in formula (Ibr) compound, the compound is-C (O) CH (NH2)CH(CH3)2The form of prodrug.
What it is included in the compounds of this invention and for the method for the present invention is formula (IIbr) compound:
Wherein:
X21brAnd X22brIndependently selected from:
Hydrogen,
Cyano,
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
Re,
-OC1-6Alkyl,
-ORe,
Naphthenic base,
Heterocyclylalkyl, and
-SH；
Y1brIt is selected from: S, NH and NRz；
R21brIt is selected from:
Amino,
Cyano,
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
Re,
-OC1-6Alkyl,
-ORe,
-NHRa,
-NRbRc,
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl,
By RdReplace 1-4 Heterocyclylalkyl,
Aryl,
By RdReplace 1-4 aryl,
Heteroaryl,
By RdReplace 1-4 heteroaryl,
- SH, and
-SRa；
R23brIt is selected from:
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, C1-4Alkoxy, oxo, phenyl, Naphthenic base, Heterocyclylalkyl ,-OH ,-NH2、-N(H)C1-4Alkyl ,-N (C1-4Alkyl)2With-CN,
Heterocyclylalkyl,
Aryl,
By RdReplace 1-4 aryl,
Heteroaryl, and
By RdReplace 1-4 heteroaryl；And R25brIt is selected from:
Amino,
-NHRa,
-NRbRc,
Aryl,
By RdReplace 1-4 aryl,
-OC1-6Alkyl,
-ORe,
- O aryl,
- O heteroaryl,
- SH, and
-SRa；
Wherein:
Each RaIndependently selected from
C1-6Alkyl,
Re,
Aryl,
By RdReplace 1-4 aryl,
Heteroaryl,
By RdReplace 1-4 heteroaryl,
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl, and
By RdReplace 1-4 Heterocyclylalkyl；
RbAnd RcIndependently selected from:
C1-6Alkyl,
Re,
Aryl,
By RdReplace 1-4 aryl,
Heteroaryl,
By RdReplace 1-4 heteroaryl；
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl, and
By RdReplace 1-4 Heterocyclylalkyl, or
RbAnd RcNitrogen connected to them and optional 1-3 additional hetero atoms are formed together Heterocyclylalkyl, optionally Substituent group below is independently selected to replace 1-5 times:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
Re,
-ORe,
Aryl,
By RdReplace 1-4 aryl,
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl, and
By RdReplace 1-4 Heterocyclylalkyl,
C1-4Alkoxy,
The C replaced by 1-6 substituent groups independently selected from the following1-4Alkoxy: fluorine, oxo ,-OH ,-COOH ,-NH2
With-CN,
- CN,
Oxo,
- OH,
- COOH,
-NO2,
-NH2,
-N(H)C1-4Alkyl,
-N(H)Re,
-N(C1-4Alkyl)2,
-ONHC(NH)NH2,
- O Heterocyclylalkyl,
- NH naphthenic base,
- NH Heterocyclylalkyl,
-S(O)2CH2CH3,
-S(O)2CH2CH2CH3,
-SO2NH2,
-S(O)2Phenyl,
-S(O)2CH3,
Benzoyl,
Benzylamino,
3- pyrrolidinylpropyl,
2- Cvclopropvlmethvl,
Cyclobutylamino,
Cyclobutyl-N (CH3)-,
Piperidyl,
Imidazole radicals,
Morpholinyl,
Morpholinyl methyl,
Methyl piperazine ylmethyl,
Methyl piperazine base,
Pyrrolidinyl,
Pyrrolidinylmethyl,
Methoxypyridylmethyl amino,
Methylpyrrole alkyl,
Difluoropyrrolidin base,
Alkyl dimethyl pyrrole,
Methylcyclopropylmethyl amino,
Hydroxymethyl-pyrrolidine base,
Fluoropyrrolidine base,
Fluorophenyl methyl amino,
Piperizinylmethyl,
Oxazolidinyl,
Methy oxetane vlmethyl,
Methyl-cyclobutyl methylamino,
Oxoimidazolidinyl and
2- hydroxyethylpiperidine base；
Each RdIndependently selected from:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
Re,
Heteroaryl,
By RxReplace 1-4 heteroaryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Naphthenic base,
By RxReplace 1-4 naphthenic base,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Heterocyclylalkyl,
By RxReplace 1-4 Heterocyclylalkyl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Aryl,
By RxReplace 1-4 aryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
C1-4Alkoxy,
Replaced 1-4 C by fluorine1-4Alkoxy,
- O aryl,
By RxReplace 1-4-O aryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- C (O) H,
-C(O)Rzz,
- C (O) aryl,
By RzzFor 1-4-C (O) aryl,
- C (O) heteroaryl,
By RzzFor 1-4-C (O) heteroaryl,
- OC (O) H,
-CO(O)Rzz,
- OC (O) aryl,
By RzzFor 1-4-CO (O) aryl,
- OC (O) heteroaryl,
By RzzFor 1-4-OC (O) heteroaryl,
Sulfydryl,
-SRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- S (O) H,
-S(O)Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2H,
-S(O)2Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2NH2,
-S(O)2NHRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl, and by 1-6 The C that a substituent group independently selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-P(O)(CH3)2,
-NHS(O)2H,
-NHS(O)2Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- NHC (O) H,
-NHC(O)Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-C(O)NH2,
-C(O)NHRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-C(O)NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl, and by 1-6 The C that a substituent group independently selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- C (O) OH,
-C(O)ORx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Oxo,
Hydroxyl,
Amino,
-NHRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl, and by 1-6 The C that a substituent group independently selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Nitro,
Cyano,
-NHC(O)NH2,
-NHC(O)NHRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-NHC(O)NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl, and by 1-6 The C that a substituent group independently selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Each ReIndependently selected from:
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
-OC1-6Alkyl,
- the OC replaced by 1-6 substituent groups independently selected from the following1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2 With-CN,
Sulfydryl,
-SRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- S (O) H,
-S(O)Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2H,
-S(O)2Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Oxo,
Hydroxyl,
Amino,
-NHRxx,
Wherein RxxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-ORxy、-COOH、-CN、-OC1-5Alkyl, by fluorine and-NRxyRxzReplace 1-6 times - OC1-5Alkyl, wherein RxyAnd RxzIndependently selected from: hydrogen, aryl, C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
-NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 The C that substituent group independently selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN, guanidine radicals,
- C (O) OH,
-C(O)ORx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH,
-COOH、-NH2With-CN,
-C(O)NH2,
-C(O)NHRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-C(O)NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 The C that substituent group independently selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN, aryl,
By RxReplace 1-4 aryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- O aryl,
By RxReplace 1-4-O aryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Heteroaryl,
By RxReplace 1-4 heteroaryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- O heteroaryl,
By RxReplace 1-4-O heteroaryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Naphthenic base,
By RxReplace 1-4 naphthenic base,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Heterocyclylalkyl,
By RxReplace 1-4 Heterocyclylalkyl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2NH2,
-S(O)2NHRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 The C that substituent group independently selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-NHS(O)2H,
-NHS(O)2Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-NHC(O)NHRxp,
Wherein RxpReplaced selected from heteroaryl, naphthenic base, Heterocyclylalkyl and by 1-4 substituent groups independently selected from the following C1-6Alkyl :-COOH ,-NH2With-CN,
-NHC(O)NRx3Rx4,
Wherein Rx3And Rx4Be each independently selected from heteroaryl, naphthenic base, Heterocyclylalkyl and by 1-6 independently selected from Under substituent group replace C1-6Alkyl :-COOH ,-NH2With-CN,
Nitro and
Cyano；With
RzIt is selected from
C1-6Alkyl,
Re,
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl, and
By RdReplace 1-4 Heterocyclylalkyl；
RzzIt is selected from
C1-6Alkyl, and
Re；
On condition that:
X21brAnd X22brIt is not all hydrogen；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, in formula (IIbr) compound, R23brFor optionally by RdReplace 1-4 aryl.
Suitably, in formula (IIbr) compound, X21brAnd X22brIt is not hydrogen.
Suitably, in formula (IIbr) compound, the compound is the form of phosphate prodrugs.
Suitably, in formula (IIbr) compound, the compound is-C (O) CH (NH2)CH(CH3)2The form of prodrug.
What it is included in the compounds of this invention and for the method for the present invention is formula (IIIbr) compound:
Wherein:
X31brAnd X32brIndependently selected from:
Hydrogen,
Cyano,
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
-OC1-6Alkyl,
Naphthenic base, and
-SH；
Y2brIt is selected from: S, NH and NRz；
R31brIt is selected from:
C1-6Alkyl,
Re1,
-OC1-6Alkyl,
-ORe1,
-NHRa1,
-NRb1Rc1,
Naphthenic base,
By Rd1Replace 1-4 naphthenic base,
Heterocyclylalkyl,
By Rd1Replace 1-4 Heterocyclylalkyl,
Aryl,
By Rd1Replace 1-4 aryl,
Heteroaryl,
By Rd1Replace 1-4 heteroaryl,
- SH, and
-SRa1；
R33brIt is selected from:
C1-6Alkyl,
Heterocyclylalkyl,
Aryl,
By Rd1Replace 1-4 aryl,
Heteroaryl, and
By Rd1Replace 1-4 heteroaryl；With
R35brIt is selected from:
Amino,
-NHRa1,
-NRb1Rc1,
Aryl,
By Rd1Replace 1-4 aryl,
-OC1-6Alkyl,
-ORe1,
- SH, and
-SRa1；
Wherein:
Each Ra1Independently selected from
C1-6Alkyl,
Re1,
Aryl,
Heteroaryl,
Naphthenic base, and
Heterocyclylalkyl；
Rb1And Rc1Independently selected from:
C1-6Alkyl,
Re1,
-ORe1,
Aryl,
By Rd1Replace 1-4 aryl,
Heteroaryl,
By Rd1Replace 1-4 heteroaryl；
Naphthenic base,
By Rd1Replace 1-4 naphthenic base,
Heterocyclylalkyl, and
By Rd1Replace 1-4 Heterocyclylalkyl, or
Rb1And Rc1Nitrogen connected to them and optional 1-3 additional hetero atoms are formed together Heterocyclylalkyl, times Choosing is replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
Re1,
Aryl,
By Rd1Replace 1-4 aryl,
Naphthenic base,
By Rd1Replace 1-4 naphthenic base,
Heterocyclylalkyl, and
By Rd1Replace 1-4 Heterocyclylalkyl, C1-4Alkoxy,
The C replaced by 1-6 substituent groups independently selected from the following1-4Alkoxy: fluorine, oxo ,-OH ,-COOH ,-NH2 With-CN,
- CN,
Oxo,
- OH,
- COOH,
-NO2,
-NH2,
-N(H)C1-4Alkyl,
-N(H)Re1,
-N(C1-4Alkyl)2,
-ONHC(NH)NH2,
- O Heterocyclylalkyl,
- NH naphthenic base,
- NH Heterocyclylalkyl,
-S(O)2CH2CH3,
-S(O)2CH2CH2CH3,
-SO2NH2,
-S(O)2Phenyl,
-S(O)2CH3,
Benzoyl,
Benzylamino,
3- pyrrolidinylpropyl,
2- Cvclopropvlmethvl,
Cyclobutylamino,
Cyclobutyl-N (CH3)-,
Piperidyl,
Imidazole radicals,
Morpholinyl,
Morpholinyl methyl,
Methyl piperazine ylmethyl,
Methyl piperazine base,
Pyrrolidinyl,
Pyrrolidinylmethyl,
Methoxypyridylmethyl amino,
Methylpyrrole alkyl,
Difluoropyrrolidin base,
Alkyl dimethyl pyrrole,
Methylcyclopropylmethyl amino,
Hydroxymethyl-pyrrolidine base,
Fluoropyrrolidine base,
Fluorophenyl methyl amino,
Piperizinylmethyl,
Oxazolidinyl,
Methy oxetane vlmethyl,
Methyl-cyclobutyl methylamino,
Oxoimidazolidinyl and
2- hydroxyethylpiperidine base；
Each Rd1Independently selected from:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
Re1,
Heteroaryl,
By RxaReplace 1-4 heteroaryl,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
Naphthenic base,
By RxaReplace 1-4 naphthenic base,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
Heterocyclylalkyl,
By RxaReplace 1-4 Heterocyclylalkyl,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
Aryl,
By RxaReplace 1-4 aryl,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
C1-4Alkoxy,
Replaced 1-4 C by fluorine1-4Alkoxy,
- O aryl,
- C (O) H,
-C(O)Rzz,
- C (O) aryl,
- C (O) heteroaryl,
- OC (O) H,
-CO(O)Rzz,
- OC (O) aryl,
- OC (O) heteroaryl,
Sulfydryl,
-SRxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
- S (O) H,
-S(O)Rxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
-S(O)2H,
-S(O)2Rxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
-S(O)2NH2,
-S(O)2NHRxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
-P(O)(CH3)2,
-NHS(O)2H,
-NHS(O)2Rxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
- NHC (O) H,
-NHC(O)Rxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
-C(O)NH2,
-C(O)NHRxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
- C (O) OH,
-C(O)ORxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
Oxo,
Hydroxyl,
Amino,
-NHRxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
Nitro,
Cyano,
-NHC(O)NH2, and
-NHC(O)NHRxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base；
Each Re1Independently selected from:
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
-OC1-6Alkyl,
- the OC replaced by 1-6 substituent groups independently selected from the following1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2 With-CN,
Sulfydryl,
-SRxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
- S (O) H,
-S(O)Rxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
-S(O)2H,
-S(O)2Rxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
Oxo,
Hydroxyl,
Amino,
-NHRxx,
Wherein RxxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-ORxy、-COOH、-CN、-OC1-5Alkyl, by fluorine and-NRxyRxzReplace 1-6 times - OC1-5Alkyl, wherein RxyAnd RxzIndependently selected from: hydrogen, aryl, C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
-NRx1xRx2x,
Wherein Rx1xAnd Rx2xIt is each independently selected from C1-4Alkyl and replaced by 1-4 substituent groups independently selected from the following C1-4Alkyl: fluorine, oxo and-OH,
Guanidine radicals,
- C (O) OH,
-C(O)ORxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
-C(O)NHRxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base and Heterocyclylalkyl,
Aryl,
By RxaReplace 1-4 aryl,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
- O aryl,
By RxaReplace 1-4-O aryl,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
Heteroaryl,
By RxaReplace 1-4 heteroaryl,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
- O heteroaryl,
- O is by RxaReplace 1-4 heteroaryl,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
Naphthenic base,
By RxReplace 1-4 naphthenic base,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Heterocyclylalkyl,
By RxReplace 1-4 Heterocyclylalkyl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2NH2,
-S(O)2NHRxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
-NHS(O)2H,
-NHS(O)2Rxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
-NHC(O)NHRxa,
Wherein RxaSelected from heteroaryl, naphthenic base and Heterocyclylalkyl,
Nitro and
Cyano；With
RzIt is selected from
C1-6Alkyl,
Re1,
Naphthenic base,
By Rd1Replace 1-4 naphthenic base,
Heterocyclylalkyl, and
By Rd1Replace 1-4 Heterocyclylalkyl；
RzzIt is selected from
C1-6Alkyl, and
Re1；
On condition that:
X31brAnd X32brIt is not all hydrogen；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, in formula (IIIbr) compound, X31brAnd X32brIt is not hydrogen.
Suitably, in formula (IIIbr) compound, R33brFor optionally by Rd1Replace 1-4 aryl.
Suitably, in formula (IIIbr) compound, the compound is the form of phosphate prodrugs.
Suitably, in formula (IIIbr) compound, the compound is-C (O) CH (NH2)CH(CH3)2The form of prodrug.
The present invention relates to the purposes of new formula (IVbbr) compound and formula (IVbbr) compound in the methods of the invention:
Wherein:
X41bbrAnd X42bbrIndependently selected from :-CN, methyl, fluorine, chlorine, bromine and iodine；
Y4bbrIt is selected from: S and NH；
R41bbrIt is selected from:
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo, C1-4Alkyl oxygen Base ,-OH ,-COOH ,-NH2、-N(H)C1-4Alkyl ,-N (C1-4Alkyl)2With-CN,
C1-4Alkyl oxy,
Replaced 1-4 C by fluorine1-4Alkyl oxy,
-N(H)C1-4Alkyl,
-N(C1-4Alkyl)2,
-SC1-4Alkyl,
Aryl,
The aryl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-OH ,-NH2 With-CN,
C1-4Alkoxy,
- CN,
Oxo,
- OH,
-NO2, and
-NH2,
Heteroaryl,
The heteroaryl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-OH ,-NH2 With-CN,
C1-4Alkoxy,
- CN,
Oxo,
- OH,
-NO2, and
-NH2,
Naphthenic base,
The naphthenic base replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-OH ,-NH2 With-CN,
C1-4Alkoxy,
- CN,
Oxo,
- OH,
-NO2, and
-NH2；
R43bbrIt is selected from:
C1-4Alkyl,
Phenyl,
The phenyl replaced by 1 or 2 substituent group independently selected from the following: fluorine ,-CH3、-CF3, chlorine ,-C (O) phenyl, pyrrole Cough up alkyl ,-P (O) (CH3)2、-C(O)NH2、-S(O)2NHCH3、-OCH2CH2N(CH3)2With-CH2C(O)NH2,
Thienyl,
Piperidyl,
Pyridine, and
The pyridine replaced by 1 or 2 substituent group independently selected from the following: fluorine ,-CH3、-CF3With-OCH3；
R44bbrAnd R45bbrIndependently selected from:
Hydrogen,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: phenyl, morpholino, triazolyl, imidazole radicals, Pyrrolidinyl ,-OC (O) NH2、-OCH2CH2NH2、-ONHC(NH2)NH2、-NHCH2C(CH3)3、-NOCH3、-NHOH、- NHCH2CH2F、-N(CH3)CH2CH2OCH3、-N(CH2CH3)2、-NCH(CH2OH)2、-N(CH2CH2OH)2、-NHCH2CH2OH、- NHCH2CH2NH2、-N(CH3)C(CH3)2CH2OH、-NHCH2CH3、-NHCH2CH2OCH3、-N(CH3)CH2CH2OH、-NHC(O)C (O)NH2、-N(CH3)CH2CH2CH2OH、-N(CH3)CH2CH(OH)CH2OH、-N(CH3)CH2CH2NH2, oxo ,-NHCH2C (CH3)2CH2OH、-OH、-NH2、-NHCH3、-NHCH2CH2CH2OH、-N(CH3)2、-N(CH3)CH2CH3、-NHOC(CH3)2NH2、- N(CH3)CH2Cyclopropyl ,-NHCH2Cyclopropyl ,-NH oxetanyl ,-NCH2CH2Triazole, piperazinyl, piperidyl, pyrazolyl, Azepine cycloheptatriene base, azetidinyl, methoxyl group and cyclopropylamino,
The wherein phenyl, morpholino, triazolyl, imidazole radicals, azepine cycloheptatriene base, azetidinyl, pyrrolidines Base, piperazinyl, piperidyl, oxetanyl, cyclopropyl and pyrazolyl are optionally by 1-4 substitutions independently selected from the following Base replaces: methyl, fluorine ,-NH2、-N(CH3)2, hydroxymethyl, oxo ,-OH and-CH2NH2,
Naphthenic base,
The naphthenic base replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH,
C1-6Alkyl, and
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine and chlorine；
Heterocyclylalkyl and
The Heterocyclylalkyl replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-OH ,-NH2 With-CN,
Aryl,
C1-4Alkoxy,
The C replaced by 1-4 substituent groups independently selected from the following1-4Alkoxy: fluorine, oxo ,-OH ,-COOH ,-NH2 With-CN,
- CN,
Oxo,
- OH,
- COOH,
-NO2,
-NH2, and
SO2NH2, or
R44bbrAnd R45bbrNitrogen connected to them and the optional 1-3 additional miscellaneous originals independently selected from O, N and S Son is formed together Heterocyclylalkyl, is optionally replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, C1-4Alkoxy, oxo, phenyl, Naphthenic base, Heterocyclylalkyl, methyl heterocycles alkyl-,-OH ,-NH2、-N(H)C1-5Alkyl, amino-heterocycles alkyl-,-N (C1-5Alkyl )2、-CN、-N(C1-4Alkyl) (CH2OCH3) and-NHC that is replaced by 1 or 2 substituent group independently selected from the following1-4Alkyl: oxygen Generation, NH2With-OH,
Aryl,
Naphthenic base,
Heterocyclylalkyl,
The Heterocyclylalkyl replaced by 1-9 substituent groups independently selected from the following: C1-6Alkyl ,-C1-6Alkyl OH, fluorine ,- C1-6Alkyl NH2, chlorine, bromine, iodine, oxo ,-OH ,-NH2With-CN,
C1-4Alkoxy,
The C replaced by 1-4 substituent groups independently selected from the following1-4Alkoxy: fluorine, oxo ,-OH ,-COOH ,-NH2 With-CN,
- CN,
Oxo,
- OH,
-OP(O)(OH)2,
- COOH,
-CONH2,
-NO2,
-NH2,
-N(H)C1-5Alkyl,
- N (H) C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, C1-4Alcoxyl Base, oxo, phenyl, naphthenic base, amino C1-4Alkoxy, Heterocyclylalkyl, methyl heterocycles alkyl-,-OH ,-NH2、-N(H)C1-4Alkane Base ,-N (C1-4Alkyl)2With-CN,
- O oxetanyl,
-ONHC(NH)NH2,
- NH cyclopropyl,
- NH oxetanyl,
-N(C1-5Alkyl)2,
-S(O)2CH2CH3,
S(O)2CH2CH2CH3,
-S(O)2CH3,
-SO2NH2,
-S(O)2Phenyl,
Benzoyl,
Benzylamino,
Propylpyrrolidinyl,
Methylcyclopropyl groups,
Cyclobutylamino,
Cyclobutyl-N (CH3)-,
Piperidyl,
Imidazole radicals,
Morpholinyl,
Morpholinyl methyl,
Methyl piperazine ylmethyl,
Methyl piperazine base,
Pyrrolidinyl,
Pyrrolidinylmethyl,
(methoxypyridylmethyl) amino,
Methylpyrrole alkyl,
Difluoropyrrolidin base,
Alkyl dimethyl pyrrole,
(methylcyclopropylmethyl) amino,
Hydroxymethyl-pyrrolidine base,
Fluoropyrrolidine base,
Fluorophenyl methyl amino,
Piperizinylmethyl,
Oxazolidinyl,
(methy oxetane ylmethyl) amino,
(methyl-cyclobutyl methyl) amino,
Oxoimidazolidinyl, and
2- hydroxyethylpiperidine base；
On condition that:
X41bbrAnd X42bbrIt is not all hydrogen, and
R44bbrAnd R45bbrIt is not all hydrogen；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, in formula (IVbbr) compound, R44bbrAnd R45bbrIt is not hydrogen.
Suitably, in formula (IVbbr) compound, R43brFor phenyl.
Suitably, in formula (IVbbr) compound, X41bbrAnd X42bbrIt is not hydrogen.
Suitably, in formula (IVbbr) compound, the compound is the form of phosphate prodrugs.
Suitably, in formula (IVbbr) compound, the compound is-C (O) CH (NH2)CH(CH3)2The form of prodrug.
The present invention relates to the purposes of new formula (Vbbr) compound and formula (Vbbr) compound in the methods of the invention:
Wherein:
Y5bbrIt is selected from: S and NH；
R50bbrIt is selected from:
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine and chlorine,
-N(H)C1-4Alkyl,
-N(C1-4Alkyl)2,
-SC1-4Alkyl,
C1-4Alkyl oxy,
Aryl,
The alkyl replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH,
C1-6Alkyl, and
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Fluorine and chlorine,
Heteroaryl,
The miscellaneous alkyl replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH,
C1-6Alkyl, and
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Fluorine and chlorine,
Naphthenic base,
The naphthenic base replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH,
C1-6Alkyl, and
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Fluorine and chlorine；
R51bbrIt is selected from:
-CH3,
Phenyl,
The phenyl replaced by 1 or 2 substituent group independently selected from the following: fluorine ,-CH3、-CF3, chlorine ,-C (O) phenyl, pyrrole Cough up alkyl ,-C (O) NH2、-S(O)2NHCH3、-OCH2CH2N(CH3)2With-CH2C(O)NH2,
Thienyl,
Piperidyl,
Pyridine, and
The pyridine replaced by 1 or 2 substituent group independently selected from the following: fluorine ,-CH3、-CF3
With-OCH3；
R53bbrAnd R54bbrIndependently selected from:
Hydrogen,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: phenyl, morpholino, triazolyl, imidazoles Base ,-CH2CH2Pyrrolidinyl ,-OC (O) NH2、-OCH2CH2NH2、-ONHC(NH2)NH2、-NHCH2C(CH3)3、-NOCH3、- NHOH、-NHCH2CH2F、-N(CH3)CH2CH2OCH3、-N(CH2CH3)2、-NCH(CH2OH)2、-N(CH2CH2OH)2、- NHCH2CH2OH、-NHCH2CH2NH2、-N(CH3)CH2(CH3)2CH2OH、-NHCH2CH3、-NHCH2CH2OCH3、-N(CH3) CH2CH2OH、-NHC(O)C(O)NH2、-N(CH3)CH2CH2CH2OH、-N(CH3)CH2CH(OH)CH2OH、-N(CH3)CH2CH2NH2、 Oxo ,-NHCH2C(CH3)2CH2OH、-OH、-NH2、-NHCH3、-NHCH2CH2CH2OH、-N(CH3)2、-N(CH3)CH2CH3、- NHOC(CH3)2NH2、-N(CH3)CH2Cyclopropyl ,-NHCH2Cyclopropyl ,-NH oxetanyl ,-NCH2CH2Triazole, piperazinyl, Piperidyl, pyrazolyl, azepine cycloheptatriene base, azetidinyl, methoxyl group and cyclopropylamino,
The wherein phenyl, morpholino, triazolyl, imidazole radicals, azepine cycloheptatriene base, azetidinyl, pyrrolidines Base, piperazinyl, piperidyl, oxetanyl, cyclopropyl and pyrazolyl are optionally by 1-4 substituent groups independently selected from the following Replace: methyl, fluorine ,-NH2、-N(CH3)2, hydroxymethyl, oxo ,-OH and-CH2NH2,
Naphthenic base,
The naphthenic base replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH,
C1-6Alkyl, and
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine and chlorine；
Heterocyclylalkyl, and
The Heterocyclylalkyl replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine and chlorine,
C1-4Alkoxy, and
- OH, or
R53bbrAnd R54bbrNitrogen connected to them and the optional 1-3 additional hetero atoms selected from O, N and S are together Heterocyclylalkyl is formed, substituent group below is optionally independently selected from and replaces 1-5 times:
Fluorine,
Chlorine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, C1-4Alkoxy, oxo, phenyl, Naphthenic base, Heterocyclylalkyl, methyl heterocycles alkyl ,-OH ,-NH2、-N(H)C1-5Alkyl, amino-heterocycles alkyl ,-N (C1-5Alkyl)2、- CN、-N(C1-4Alkyl) (CH2OCH3) and-NHC that is replaced by 1 or 2 substituent group independently selected from the following1-4Alkyl: oxo, NH2With-OH,
Heterocyclylalkyl,
The Heterocyclylalkyl replaced by 1-9 substituent groups independently selected from the following: C1-6Alkyl ,-C1-6Alkyl OH, fluorine ,- C1-6Alkyl NH2, chlorine, oxo and-OH, C1-4Alkoxy,
The C replaced by 1-4 substituent groups independently selected from the following1-4Alkoxy: fluorine, oxo ,-OH ,-COOH ,-NH2 With-CN,
- CN,
Oxo,
- OH,
-OP(O)(OH)2,
- COOH,
-CONH2,
-NH2,
-N(H)C1-4Alkyl,
- N (H) C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Fluorine, chlorine, C1-4Alkoxy, oxo, phenyl, naphthenic base, amino C1-4Alkoxy, Heterocyclylalkyl, methyl heterocycles alkane Base ,-OH ,-NH2、-N(H)C1-4Alkyl ,-N (C1-4Alkyl)2With-CN,
- O oxetanyl,
-ONHC(NH)NH2,
- NH cyclopropyl,
- NH oxetanyl,
-N(C1-4Alkyl)2,
-S(O)2CH2CH3,
S(O)2CH2CH2CH3,
-S(O)2CH3,
-S(O)2Phenyl,
Benzoyl,
Benzylamino,
Propylpyrrolidinyl,
Methylcyclopropyl groups,
Cyclobutylamino,
Cyclobutyl-N (CH3)-,
Piperidyl,
Imidazole radicals,
Morpholinyl,
Morpholinyl methyl,
Methyl piperazine ylmethyl,
Methyl piperazine base
Pyrrolidinyl,
Pyrrolidinylmethyl,
(methoxypyridylmethyl) amino,
Methylpyrrole alkyl,
Difluoropyrrolidin base,
Alkyl dimethyl pyrrole,
(methylcyclopropylmethyl) amino,
Hydroxymethyl-pyrrolidine base,
Fluoropyrrolidine base,
Fluorophenyl methyl amino,
Piperizinylmethyl,
Oxazolidinyl,
(methy oxetane ylmethyl) amino,
(methyl-cyclobutyl methyl) amino,
Oxoimidazolidinyl, and
2- hydroxyethylpiperidine base；
On condition that:
R53bbrAnd R54bbrIt is not all hydrogen；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, in formula (Vbbr) compound, R53bbrAnd R54bbrIt is not hydrogen.
Suitably, in formula (Vbbr) compound, R51bbrFor phenyl.
Suitably, in formula (Vbbr) compound, the compound is the form of phosphate prodrugs.
Suitably, in formula (Vbbr) compound, the compound is-C (O) CH (NH2)CH(CH3)2The form of prodrug.
The present invention relates to the purposes of new formula (VIbbr) compound and formula (VIbbr) compound in the methods of the invention:
Wherein:
R60bbrIt is selected from:
C1-3Alkyl,
The C replaced by 1-6 substituent groups independently selected from the following1-3Alkyl: fluorine and chlorine,
-N(H)C1-3Alkyl,
-N(C1-3Alkyl)2,
-SC1-4Alkyl,
C1-3Alkyl oxy,
Aryl,
The aryl replaced by 1-3 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH, and
C1-3Alkyl,
Heteroaryl,
The heteroaryl replaced by 1-3 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH, and
C1-3Alkyl,
Naphthenic base,
The naphthenic base replaced by 1-3 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH, and
C1-3Alkyl；
R61bbrIt is selected from:
-CH3,
Phenyl,
The phenyl replaced by 1 or 2 substituent group independently selected from the following:
Fluorine ,-CH3、-CF3, chlorine ,-C (O) phenyl, pyrrolidinyl ,-C (O) NH2、-S(O)2NHCH3、-OCH2CH2N(CH3)2 With-CH2C(O)NH2,
Thienyl,
Piperidyl,
Pyridine, and
The pyridine replaced by 1 or 2 substituent group independently selected from the following:
Fluorine ,-CH3、-CF3With-OCH3；
R63bbrAnd R64bbrIndependently selected from:
Hydrogen,
C1-4Alkyl,
The C replaced by 1-4 substituent groups independently selected from the following1-4Alkyl:
Phenyl, morpholino, triazolyl, imidazole radicals ,-CH2CH2Pyrrolidinyl ,-OC (O) NH2、-OCH2CH2NH2、-ONHC (NH2)NH2、-NHCH2C(CH3)3、-NOCH3、-NHOH、-NHCH2CH2F、-N(CH3)CH2CH2OCH3、-N(CH2CH3)2、-NCH (CH2OH)2、-N(CH2CH2OH)2、-NHCH2CH2OH、-NHCH2CH2NH2、-N(CH3)CH2(CH3)2CH2OH、-NHCH2CH3、- NHCH2CH2OCH3、-N(CH3)CH2CH2OH、-NHC(O)C(O)NH2、-N(CH3)CH2CH2CH2OH、-N(CH3)CH2CH(OH) CH2OH、-N(CH3)CH2CH2NH2, oxo ,-NHCH2C(CH3)2CH2OH、-OH、-NH2、-NHCH3、-NHCH2CH2CH2OH、-N (CH3)2、-N(CH3)CH2CH3、-NHOC(CH3)2NH2、-N(CH3)CH2Cyclopropyl ,-NHCH2Cyclopropyl ,-NH oxetanes Base ,-NCH2CH2Triazole, piperazinyl, piperidyl, pyrazolyl, azepine cycloheptatriene base, azetidinyl, methoxyl group and cyclopropyl Base amino,
The wherein phenyl, morpholino, triazolyl, imidazole radicals, azepine cycloheptatriene base, azetidinyl, pyrrolidines Base, piperazinyl, piperidyl, oxetanyl, cyclopropyl and pyrazolyl are optionally by 1-4 substituent groups independently selected from the following Replace: methyl, fluorine ,-NH2、-N(CH3)2, hydroxymethyl, oxo ,-OH and-CH2NH2,
Naphthenic base,
The naphthenic base replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH, and
C1-6Alkyl,
Heterocyclylalkyl, and
The Heterocyclylalkyl replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH, and
C1-6Alkyl, or
R63bbrAnd R64bbrNitrogen connected to them and the optional 1-3 hetero atoms additional independently selected from O, N and S It is formed together Heterocyclylalkyl, is optionally replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH,
-OP(O)(OH)2,
- CN,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, C1-4Alkoxy, oxo, phenyl, Naphthenic base, Heterocyclylalkyl, methyl heterocycles alkyl ,-OH ,-NH2、-N(H)C1-5Alkyl, amino-heterocycles alkyl ,-N (C1-5Alkyl)2、- CN、-N(C1-4Alkyl) (CH2OCH3) and-NHC that is replaced by 1 or 2 independently selected from following substituent group1-4Alkyl: oxo, NH2 With-OH,
Heterocyclylalkyl,
The Heterocyclylalkyl replaced by 1-9 substituent groups independently selected from the following: C1-6Alkyl ,-C1-6Alkyl OH, fluorine, chlorine, Oxo and-OH,
C1-4Alkoxy,
The C replaced by 1-4 substituent groups independently selected from the following1-4Alkoxy: fluorine, oxo ,-OH ,-COOH ,-NH2 With-CN,
Oxo,
-NH2,
-N(H)C1-6Alkyl,
- N (H) C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Fluorine, chlorine, C1-4Alkoxy, oxo, phenyl, naphthenic base, amino C1-4Alkoxy, Heterocyclylalkyl, methyl heterocycles alkane Base ,-OH ,-NH2、-N(H)C1-4Alkyl ,-N (C1-4Alkyl)2With-CN,
-ONHC(NH)NH2,
- O oxetanyl,
-ONHC(NH)NH2,
- NH cyclopropyl,
- NH oxetanyl,
-N(C1-4Alkyl)2,
-S(O)2CH2CH3,
S(O)2CH2CH2CH3,
-S(O)2CH3,
-S(O)2Phenyl,
Benzoyl,
Benzylamino,
Propylpyrrolidinyl,
Methylcyclopropyl groups,
Cyclobutylamino,
Cyclobutyl-N (CH3)-,
Piperidyl,
Imidazole radicals,
Morpholinyl,
Morpholinyl methyl,
Methyl piperazine ylmethyl,
Methyl piperazine base,
Pyrrolidinyl,
Pyrrolidinylmethyl,
(methoxypyridylmethyl) amino,
Methylpyrrole alkyl,
Difluoropyrrolidin base,
Alkyl dimethyl pyrrole,
(methylcyclopropylmethyl) amino,
Hydroxymethyl-pyrrolidine base,
Fluoropyrrolidine base,
(fluorophenyl methyl) amino,
Piperizinylmethyl,
Oxazolidinyl,
(methy oxetane ylmethyl) amino,
(methyl-cyclobutyl methyl) amino,
Oxoimidazolidinyl, and
2- hydroxyethylpiperidine base；
On condition that:
R63bbrAnd R64bbrIt is not all hydrogen；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, in formula (VIbbr) compound, R63bbrAnd R64bbrIt is not hydrogen.
Suitably, in formula (VIbbr) compound, R61bbrFor phenyl.
Suitably, in formula (VIbbr) compound, the compound is the form of phosphate prodrugs.
Suitably, in formula (VIbbr) compound, the compound is-C (O) CH (NH2)CH(CH3)2The form of prodrug.
The present invention relates to the purposes of new formula (VIIbbr) compound and formula (VIIbbr) compound in the methods of the invention:
Wherein:
R70bbrIt is selected from:
Ethyl,
Replaced 1-4 ethyl by fluorine,
-NCH3,
-SCH3,
Ethyoxyl,
Methoxyl group,
Propoxyl group,
Phenyl,
Furyl,
Cyclopropyl and
Replaced 1 or 2 cyclopropyl by fluorine；
R71bbrIt is selected from:
Phenyl,
The phenyl replaced by 1 or 2 substituent group independently selected from the following: fluorine ,-CH3、-CF3, chlorine ,-C (O) phenyl, pyrrole Cough up alkyl ,-C (O) NH2、-S(O)2NHCH3、-OCH2CH2N(CH3)2With-CH2C(O)NH2,
Thienyl,
Piperidyl,
Pyridine, and
The pyridine replaced by 1 or 2 substituent group independently selected from the following: fluorine ,-CH3、-CF3With-OCH3；With
R72bbrAnd R73bbrIndependently selected from:
Hydrogen,
C1-4Alkyl,
The C replaced by 1-4 substituent groups independently selected from the following1-4Alkyl:
Phenyl, morpholino, triazolyl, imidazole radicals ,-CH2CH2Pyrrolidinyl ,-OC (O) NH2、-OCH2CH2NH2、-ONHC (NH2)NH2、-NHCH2C(CH3)3、-NOCH3、-NHOH、-NHCH2CH2F、-N(CH3)CH2CH2OCH3、-N(CH2CH3)2、-NCH (CH2OH)2、-N(CH2CH2OH)2、-NHCH2CH2OH、-NHCH2CH2NH2、-N(CH3)CH2(CH3)2CH2OH、-NHCH2CH3、- NHCH2CH2OCH3、-N(CH3)CH2CH2OH、-NHC(O)C(O)NH2、-N(CH3)CH2CH2CH2OH、-N(CH3)CH2CH(OH) CH2OH、-N(CH3)CH2CH2NH2, oxo ,-NHCH2C(CH3)2CH2OH、-OH、-NH2、-NHCH3、-NHCH2CH2CH2OH、-N (CH3)2、-N(CH3)CH2CH3、-NHOC(CH3)2NH2、-N(CH3)CH2Cyclopropyl ,-NHCH2Cyclopropyl ,-NH oxetanes Base ,-NCH2CH2Triazole, piperazinyl, piperidyl, pyrazolyl, azepine cycloheptatriene base, azetidinyl, methoxyl group and cyclopropyl Base amino,
The wherein phenyl, morpholino, triazolyl, imidazole radicals, azepine cycloheptatriene base, azetidinyl, pyrrolidines Base, piperazinyl, piperidyl, oxetanyl, cyclopropyl and pyrazolyl are optionally by 1-4 substituent groups independently selected from the following Replace: methyl, fluorine ,-NH2、-N(CH3)2, hydroxymethyl, oxo ,-OH and-CH2NH2,
Cyclobutyl,
Aminocyclobutyl,
Tetrahydrofuran,
5- oxa- -2- azaspiro [3.4] octyl, and
8- azabicyclo [3.2.1] octyl, or
R72bbrAnd R73bbrNitrogen connected to them and optional 1-3 additional hetero atoms are formed together Heterocyclylalkyl, It is selected from:
Pyrrolidinyl,
Pyrrolo- [3,4-c] pyrazolyl,
Piperidyl,
Isosorbide-5-Nitrae-Diazesuberane base,
Piperazinyl,
6,7- dihydros-triazol [4,5-c] pyridyl group,
2,9- diaza spiros [5.5] undecyl,
2,8- diaza spiros [4.5] decyl,
Octahydro -1H- pyrrolo- [1,2a] [Isosorbide-5-Nitrae] diaza cycloheptatriene base,
Oxa--diaza spiro [4.5] decyl,
Oxazolyl,
Morpholinyl,
1- oxa- -6- azaspiro [3.4] octyl,
2- oxa- -6- azaspiro [3.4] octyl,
1,7- diaza spiro [3.5] nonyl,
2,7- diaza spiros [3.5] nonyl,
2,6- diaza spiros [3.4] octyl,
Azetidinyl,
Hexahydropyrrolo simultaneously [3,4-b] oxazines base,
Dihydro phthalazinyl,
Diazabicyclo heptane base,
1,8- diaza spiro [4.5] decyl, and
5- oxa- -2- azaspiro [3.4] octyl,
All of which is optionally replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Oxo,
- OH,
- CN,
-CH3,
-CH2OH,
Methoxyl group,
-CH2CH3,
-C(O)CH3,
-C(O)NH2,
-OCH2CH2OH,
-OCH2CH2NH2,
-ONHC(NH)NH2,
-OC(O)NH2,
- O oxetanyl,
-CH2CH2OH,
-CH2CH2CH2OH,
-CH2CH2CH3,
-CH2CH2OCH3,
-CH2CH(OH)CH3,
-CH2CH(OH)CH2OH,
-CH2C(O)OCH3,
-CH2C(O)NH2,
-C(O)CH(CH3)2,
-CH2CH2N(CH3)2,
-CH2CH2NHCH2CH3,
-CH2CH2CH2N(CH3)2,
-CH2CH2NHCH2C(CH3)3,
-CH2CH2N(CH3)CH2OCH3,
-C(CH3)2CH2OH,
-CH2C(CH3)2OH,
-CH2C(CH3)2OCH3,
-C(O)CH2OH,
-CH2Isothiazolyl,
-CH2Thiazolyl,
-CH2Pyrazolyl,
-CH2Imidazole radicals,
-CH2Pyridyl group,
-CH2Oxazolyl,
-CH2Pyrrole radicals,
-CH2Isoxazolyl,
-CH2Furyl,
-CH2CH2Morpholinyl,
-CH2CH2Pyrrolidinyl,
-CH2CH2Pyrrolidinyl CH3,
-CH2CH2CH2Pyrrolidinyl,
- C (O) phenyl,
- C (O) C (THP trtrahydropyranyl) NH2,
-NH2,
-NHCH3,
-N(CH3)2,
-NHC(O)CH3,
-NHCH2CHF2,
-NHCH2C(CH3)3,
-NHCH2CH(CH3)2,
-NHCH2CH2OCH3,
-NHCH2CH2OH,
-NHCH2CH2NH2,
-NHCH2C (O) OH,
-NHC(O)CH2NH2,
-NHC(O)CH2CH2CH2NH2,
-NHCH2C(O)NH2,
-NHCH2C(OH)(CH3)2,
-NHC(O)CH(CH3)NH2,
-NHC(O)OCH(CH3)NH2,
-NHC(O)CH(CH3)2,
-NHC(O)C(CH3)2NH2,
-NHC(O)CH2OH,
-NHC(O)CH(CH2OH)NH2,
- NHC (O) (oxetanyl) NH2,
-NHC(O)OC(CH3)3,
-NHC(CH3)2C(O)OCH3,
- NH cyclopropyl,
- NH oxetanyl,
-CH2NH2,
-CH2CH2NH2,
-CH2CH2CH2NH2,
-CH2NHCH2C(CH3)3,
-CH2NHC(O)C(CH3)3,
-CH2NHC(O)CH2NH2,
-CH2NHC(O)CH2OH,
-CH2N(CH3)2,
-CH2NHCH3,
-CH2N(CH2CH3)2,
-CH2CH2N(CH3)2,
-S(O)2CH2CH3,
-S(O)2CH2CH2CH3,
-S(O)2Phenyl,
-S(O)2CH3,
Benzoyl,
Benzylamino,
3- pyrrolidinylpropyl,
2- Cvclopropvlmethvl,
Cyclobutylamino,
Cyclobutyl-N (CH3)-,
Piperidyl,
Imidazole radicals,
Morpholinyl,
Morpholinyl methyl,
Methyl piperazine ylmethyl,
Methyl piperazine base,
Pyrrolidinyl,
Pyrrolidinylmethyl,
Methoxypyridylmethyl amino,
Methylpyrrole alkyl,
Difluoropyrrolidin base,
Alkyl dimethyl pyrrole,
Methylcyclopropylmethyl amino,
Hydroxymethyl-pyrrolidine base,
Fluoropyrrolidine base,
Fluorophenyl methyl amino,
Piperizinylmethyl,
Oxazolidinyl,
Methy oxetane vlmethyl,
Methyl-cyclobutyl methylamino,
Oxoimidazolidinyl, and
2- hydroxyethylpiperidine base；
On condition that:
R72bbrAnd R73bbrIt is not all hydrogen,
Or its pharmaceutically acceptable salt or prodrug.
Suitably, in formula (VIIbbr) compound, R72bbrAnd R73bbrIt is not hydrogen.
Suitably, in formula (VIIbbr) compound, R71bbrFor phenyl.
Suitably, in formula (VIIbbr) compound, the compound is the form of phosphate prodrugs.
Suitably, in formula (VIIbbr) compound, the compound is-C (O) CH (NH2)CH(CH3)2The shape of prodrug Formula.
The present invention relates to the purposes of new formula (Qb) compound and formula (Qb) compound in the methods of the invention:
Wherein:
R70a”It is selected from:
Ethyl,
-OCH3,
-CH2CF3, and
Cyclopropyl；
R71a”It is selected from:
Phenyl,
The phenyl replaced by 1 or 2 substituent group independently selected from the following:
Fluorine ,-CH3、-CF3And chlorine,
Pyridine, and
The pyridine replaced by 1 or 2 substituent group independently selected from the following:
Fluorine ,-CH3、-CF3With-OCH3；With
R72a”And R73a”Independently selected from:
Hydrogen,
C1-4Alkyl,
The C replaced by 1-4 substituent groups independently selected from the following1-4Alkyl: phenyl, morpholino, triazolyl, imidazoles Base ,-CH2CH2Pyrrolidinyl ,-OC (O) NH2、-OCH2CH2NH2、-ONHC(NH2)NH2、-NHCH2C(CH3)3、-NOCH3、- NHOH、-NHCH2CH2F、-N(CH3)CH2CH2OCH3、-N(CH2CH3)2、-NCH(CH2OH)2、-N(CH2CH2OH)2、- NHCH2CH2OH、-NHCH2CH2NH2、-N(CH3)CH2(CH3)2CH2OH、-NHCH2CH3、-NHCH2CH2OCH3、-N(CH3) CH2CH2OH、-NHC(O)C(O)NH2、-N(CH3)CH2CH2CH2OH、-N(CH3)CH2CH(OH)CH2OH、-N(CH3)CH2CH2NH2、 Oxo ,-NHCH2C(CH3)2CH2OH、-OH、-NH2、-NHCH3、-NHCH2CH2CH2OH、-N(CH3)2、-N(CH3)CH2CH3、- NHOC(CH3)2NH2、-N(CH3)CH2Cyclopropyl ,-NHCH2Cyclopropyl ,-NH oxetanyl ,-NCH2CH2Triazole, piperazinyl, Piperidyl, pyrazolyl, azepine cycloheptatriene base, azetidinyl, methoxyl group and cyclopropylamino,
The wherein phenyl, morpholino, triazolyl, imidazole radicals, azepine cycloheptatriene base, azetidinyl, pyrrolidines Base piperazinyl, piperidyl, oxetanyl, cyclopropyl and pyrazolyl are optionally by 1-4 substituent groups independently selected from the following Replace: methyl, fluorine ,-NH2、-N(CH3)2, hydroxymethyl, oxo ,-OH and-CH2NH2,
Cyclobutyl,
Aminocyclobutyl,
Tetrahydrofuran,
5- oxa- -2- azaspiro [3.4] octyl, and
8- azabicyclo [3.2.1] octyl, or
R72a”And R73a”Nitrogen connected to them and the optional 1-3 additional hetero atoms independently selected from O, N and S It is formed together Heterocyclylalkyl, is selected from:
Pyrrolidinyl,
Pyrrolo- [3,4-c] pyrazolyl,
Piperidyl,
Isosorbide-5-Nitrae-Diazesuberane base,
Piperazinyl,
6,7- dihydros-triazol [4,5-c] pyridyl group,
2,9- diaza spiros [5.5] undecyl,
2,8- diaza spiros [4.5] decyl,
Octahydro -1H- pyrrolo- [1,2a] [Isosorbide-5-Nitrae] diaza cycloheptatriene base,
Oxa--diaza spiro [4.5] decyl,
Oxazolyl,
Morpholinyl,
1- oxa- -6- azaspiro [3.4] octyl,
2- oxa- -6- azaspiro [3.4] octyl,
1,7- diaza spiro [3.5] nonyl,
2,7- diaza spiros [3.5] nonyl,
2,6- diaza spiros [3.4] octyl,
Azetidinyl,
Hexahydropyrrolo simultaneously [3,4-b] oxazines base,
Dihydro phthalazinyl,
Diazabicyclo heptane base,
1,8- diaza spiro [4.5] decyl, and
5- oxa- -2- azaspiro [3.4] octyl,
All of which is optionally replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Oxo,
- OH,
-OP(O)(OH)2,
- CN,
-CH3,
-CH2OH,
Methoxyl group,
-CH2CH3,
-C(O)CH3,
-C(O)NH2,
-OCH2CH2OH,
-OCH2CH2NH2,
-ONHC(NH)NH2,
-OC(O)NH2,
- O oxetanyl,
-CH2CH2OH,
-CH2CH2CH2OH,
-CH2CH2CH3,
-CH2CH2OCH3,
-CH2CH(OH)CH3,
-CH2CH(OH)CH2OH,
-CH2C(O)OCH3,
-CH2C(O)NH2,
-C(O)CH(CH3)2,
-CH2CH2N(CH3)2,
-CH2CH2NHCH2CH3,
-CH2CH2CH2N(CH3)2,
-CH2CH2NHCH2C(CH3)3,
-CH2CH2N(CH3)CH2OCH3,
-C(CH3)2CH2OH,
-CH2C(CH3)2OH,
-CH2C(CH3)2OCH3,
-C(O)CH2OH,
-CH2Isothiazolyl,
-CH2Thiazolyl,
-CH2Pyrazolyl,
-CH2Imidazole radicals,
-CH2Pyridyl group,
-CH2Oxazolyl,
-CH2Pyrrole radicals,
-CH2Isoxazolyl,
-CH2Furyl,
-CH2CH2Morpholinyl,
-CH2CH2Pyrrolidinyl,
-CH2CH2Pyrrolidinyl CH3,
-CH2CH2CH2Pyrrolidinyl,
- C (O) phenyl,
- C (O) C (THP trtrahydropyranyl) NH2,
-NH2,
-NHCH3,
-N(CH3)2,
-NHC(O)CH3,
-NHCH2CHF2,
-NHCH2C(CH3)3,
-NHCH2CH(CH3)2,
-NHCH2CH2OCH3,
-NHCH2CH2OH,
-NHCH2CH2NH2,
-NHCH2C (O) OH,
-NHC(O)CH2NH2,
-NHC(O)CH2CH2CH2NH2,
-NHCH2C(O)NH2,
-NHCH2C(OH)(CH3)2,
-NHC(O)CH(CH3)NH2,
-NHC(O)OCH(CH3)NH2,
-NHC(O)CH(CH3)2,
-NHC(O)C(CH3)2NH2,
-NHC(O)CH2OH,
-NHC(O)CH(CH2OH)NH2,
- NHC (O) (oxetanyl) NH2,
-NHC(O)OC(CH3)3,
-NHC(CH3)2C(O)OCH3,
- NH cyclopropyl,
- NH oxetanyl,
-CH2NH2,
-CH2CH2NH2,
-CH2CH2CH2NH2,
-CH2NHCH2C(CH3)3,
-CH2NHC(O)C(CH3)3,
-CH2NHC(O)CH2NH2,
-CH2NHC(O)CH2OH,
-CH2N(CH3)2,
-CH2NHCH3,
-CH2N(CH2CH3)2,
-CH2CH2N(CH3)2,
-S(O)2CH2CH3,
-S(O)2CH2CH2CH3,
-S(O)2Phenyl,
-S(O)2CH3,
Benzoyl,
Benzylamino,
Propylpyrrolidinyl,
Methylcyclopropyl groups,
Cyclobutylamino,
Cyclobutyl-N (CH3)-,
Piperidyl,
Imidazole radicals,
Morpholinyl,
Morpholinyl methyl,
Methyl piperazine ylmethyl,
Methyl piperazine base,
Pyrrolidinyl,
Pyrrolidinylmethyl,
(methoxypyridylmethyl) amino,
Methylpyrrole alkyl,
Difluoropyrrolidin base,
Alkyl dimethyl pyrrole,
(methylcyclopropylmethyl) amino,
Hydroxymethyl-pyrrolidine base,
Fluoropyrrolidine base,
(fluorophenyl methyl) amino,
Piperizinylmethyl,
Oxazolidinyl,
(methy oxetane ylmethyl) amino,
(methyl-cyclobutyl methyl) amino,
Oxoimidazolidinyl, and
2- hydroxyethylpiperidine base；
On condition that:
R72a”And R73a”It is not all hydrogen；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, in formula (Qb) compound, R72a”And R73a”It is not hydrogen.
Suitably, in formula (Qb) compound, R71a”For phenyl.
Suitably, in formula (Qb) compound, the compound is the form of phosphate prodrugs.
Suitably, in formula (Qb) compound, the compound is-C (O) CH (NH2)CH(CH3)2The form of prodrug.
The present invention relates to the purposes of new formula (Qb1) compound and formula (Qb1) compound in the methods of the invention:
Wherein:
R70b”It is selected from:
Ethyl,
-OCH3,
-CH2CF3, and
Cyclopropyl；
R71b”It is selected from:
Phenyl,
The phenyl replaced by 1 or 2 substituent group independently selected from the following:
Fluorine ,-CH3、-CF3And chlorine,
Pyridine, and
The pyridine replaced by 1 or 2 substituent group independently selected from the following:
Fluorine ,-CH3、-CF3With-OCH3；With
R72b”And R73b”Independently selected from:
C1-4Alkyl,
The C replaced by 1-4 substituent groups independently selected from the following1-4Alkyl:
Phenyl, morpholino, triazolyl, imidazole radicals ,-CH2CH2Pyrrolidinyl ,-OC (O) NH2、-OCH2CH2NH2、-ONHC (NH2)NH2、-NHCH2C(CH3)3、-NOCH3、-NHOH、-NHCH2CH2F、-N(CH3)CH2CH2OCH3、-N(CH2CH3)2、-NCH (CH2OH)2、-N(CH2CH2OH)2、-NHCH2CH2OH、-NHCH2CH2NH2、-N(CH3)CH2(CH3)2CH2OH、-NHCH2CH3、- NHCH2CH2OCH3、-N(CH3)CH2CH2OH、-NHC(O)C(O)NH2、-N(CH3)CH2CH2CH2OH、-N(CH3)CH2CH(OH) CH2OH、-N(CH3)CH2CH2NH2, oxo ,-NHCH2C(CH3)2CH2OH、-OH、-NH2、-NHCH3、-NHCH2CH2CH2OH、-N (CH3)2、-N(CH3)CH2CH3、-NHOC(CH3)2NH2、-N(CH3)CH2Cyclopropyl ,-NHCH2Cyclopropyl ,-NH oxetanes Base ,-NCH2CH2Triazole, piperazinyl, piperidyl, pyrazolyl, azepine cycloheptatriene base, azetidinyl, methoxyl group and cyclopropyl Base amino,
The wherein phenyl, morpholino, triazolyl, imidazole radicals, azepine cycloheptatriene base, azetidinyl, pyrrolidines Base piperazinyl, piperidyl, oxetanyl, cyclopropyl and pyrazolyl are optionally by 1-4 substituent groups independently selected from the following Replace: methyl, fluorine ,-NH2、-N(CH3)2, hydroxymethyl, oxo ,-OH and-CH2NH2,
Cyclobutyl,
Aminocyclobutyl,
Tetrahydrofuran,
5- oxa- -2- azaspiro [3.4] octyl, and
8- azabicyclo [3.2.1] octyl, or
R72b”And R73b”Nitrogen connected to them and optional 1-3 additional hetero atoms are formed together Heterocyclylalkyl, It is selected from:
Pyrrolidinyl,
Pyrrolo- [3,4-c] pyrazolyl,
Piperidyl,
Isosorbide-5-Nitrae-Diazesuberane base,
Piperazinyl,
6,7- dihydros-triazol [4,5-c] pyridyl group,
2,9- diaza spiros [5.5] undecyl,
2,8- diaza spiros [4.5] decyl,
Octahydro -1H- pyrrolo- [1,2a] [Isosorbide-5-Nitrae] diaza cycloheptatriene base,
Oxa--diaza spiro [4.5] decyl,
Oxazolyl,
Morpholinyl,
1- oxa- -6- azaspiro [3.4] octyl,
2- oxa- -6- azaspiro [3.4] octyl,
1,7- diaza spiro [3.5] nonyl,
2,7- diaza spiros [3.5] nonyl,
2,6- diaza spiros [3.4] octyl,
Azetidinyl,
Hexahydropyrrolo simultaneously [3,4-b] oxazines base,
Dihydro phthalazinyl,
Diazabicyclo heptane base,
1,8- diaza spiro [4.5] decyl, and
5- oxa- -2- azaspiro [3.4] octyl,
All of which is optionally replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Oxo,
- OH,
- CN,
-CH3,
-CH2OH,
Methoxyl group,
-CH2CH3,
-C(O)CH3,
-C(O)NH2,
-OCH2CH2OH,
-OCH2CH2NH2,
-ONHC(NH)NH2,
-OC(O)NH2,
- O oxetanyl,
-CH2CH2OH,
-CH2CH2CH2OH,
-CH2CH2CH3,
-CH2CH2OCH3,
-CH2CH(OH)CH3,
-CH2CH(OH)CH2OH,
-CH2C(O)OCH3,
-CH2C(O)NH2,
-C(O)CH(CH3)2,
-CH2CH2N(CH3)2,
-CH2CH2NHCH2CH3,
-CH2CH2CH2N(CH3)2,
-CH2CH2NHCH2C(CH3)3,
-CH2CH2N(CH3)CH2OCH3,
-C(CH3)2CH2OH,
-CH2C(CH3)2OH,
-CH2C(CH3)2OCH3,
-C(O)CH2OH,
-CH2Isothiazolyl,
-CH2Thiazolyl,
-CH2Pyrazolyl,
-CH2Imidazole radicals,
-CH2Pyridyl group,
-CH2Oxazolyl,
-CH2Pyrrole radicals,
-CH2Isoxazolyl,
-CH2Furyl,
-CH2CH2Morpholinyl,
-CH2CH2Pyrrolidinyl,
-CH2CH2Pyrrolidinyl CH3,
-CH2CH2CH2Pyrrolidinyl,
- C (O) phenyl,
- C (O) C (THP trtrahydropyranyl) NH2,
-NH2,
-NHCH3,
-N(CH3)2,
-NHC(O)CH3,
-NHCH2CHF2,
-NHCH2C(CH3)3,
-NHCH2CH(CH3)2,
-NHCH2CH2OCH3,
-NHCH2CH2OH,
-NHCH2CH2NH2,
-NHCH2C (O) OH,
-NHC(O)CH2NH2,
-NHC(O)CH2CH2CH2NH2,
-NHCH2C(O)NH2,
-NHCH2C(OH)(CH3)2,
-NHC(O)CH(CH3)NH2,
-NHC(O)OCH(CH3)NH2,
-NHC(O)CH(CH3)2,
-NHC(O)C(CH3)2NH2,
-NHC(O)CH2OH,
-NHC(O)CH(CH2OH)NH2,
- NHC (O) (oxetanyl) NH2,
-NHC(O)OC(CH3)3,
-NHC(CH3)2C(O)OCH3,
- NH cyclopropyl,
- NH oxetanyl,
-CH2NH2,
-CH2CH2NH2,
-CH2CH2CH2NH2,
-CH2NHCH2C(CH3)3,
-CH2NHC(O)C(CH3)3,
-CH2NHC(O)CH2NH2,
-CH2NHC(O)CH2OH,
-CH2N(CH3)2,
-CH2NHCH3,
-CH2N(CH2CH3)2,
-CH2CH2N(CH3)2,
-S(O)2CH2CH3,
-S(O)2CH2CH2CH3,
-S(O)2Phenyl,
-S(O)2CH3,
Benzoyl,
Benzylamino,
3- pyrrolidinylpropyl,
2- Cvclopropvlmethvl,
Cyclobutylamino,
Cyclobutyl-N (CH3)-,
Piperidyl,
Imidazole radicals,
Morpholinyl,
Morpholinyl methyl,
Methyl piperazine ylmethyl,
Methyl piperazine base,
Pyrrolidinyl,
Pyrrolidinylmethyl,
Methoxypyridylmethyl amino,
Methylpyrrole alkyl,
Difluoropyrrolidin base,
Alkyl dimethyl pyrrole,
Methylcyclopropylmethyl amino,
Hydroxymethyl-pyrrolidine base,
Fluoropyrrolidine base,
Fluorophenyl methyl amino,
Piperizinylmethyl,
Oxazolidinyl,
Methy oxetane vlmethyl,
Methyl-cyclobutyl methylamino,
Oxoimidazolidinyl, and
2- hydroxyethylpiperidine base；
On condition that:
R72b”And R73b”It is not all unsubstituted alkyl；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, in formula (Qb1) compound, R71b”For phenyl.
Suitably, in formula (Qb1) compound, the compound is the form of phosphate prodrugs.
Suitably, in formula (Qb1) compound, the compound is-C (O) CH (NH2)CH(CH3)2The form of prodrug.
The present invention relates to the purposes of new formula (Qb2) compound and formula (Qb2) compound in the methods of the invention:
Wherein:
R70c”It is selected from:
Ethyl,
-OCH3,
-CH2CF3, and
Cyclopropyl；
R71c”It is selected from:
Phenyl,
The phenyl replaced by 1 or 2 substituent group independently selected from the following:
Fluorine ,-CH3、-CF3And chlorine,
Pyridine, and
The pyridine replaced by 1 or 2 substituent group independently selected from the following:
Fluorine ,-CH3、-CF3With-OCH3；With
R72c”And R73c”Nitrogen connected to them and optional 1-3 additional hetero atoms are formed together Heterocyclylalkyl, It is selected from:
Pyrrolidinyl,
Pyrrolo- [3,4-c] pyrazolyl,
Piperidyl,
Isosorbide-5-Nitrae-Diazesuberane base,
Piperazinyl,
6,7- dihydros-triazol [4,5-c] pyridyl group,
2,9- diaza spiros [5.5] undecyl,
2,8- diaza spiros [4.5] decyl,
Octahydro -1H- pyrrolo- [1,2a] [Isosorbide-5-Nitrae] diaza cycloheptatriene base,
Oxa--diaza spiro [4.5] decyl,
Oxazolyl,
Morpholinyl,
1- oxa- -6- azaspiro [3.4] octyl,
2- oxa- -6- azaspiro [3.4] octyl,
1,7- diaza spiro [3.5] nonyl,
2,7- diaza spiros [3.5] nonyl,
2,6- diaza spiros [3.4] octyl,
Azetidinyl,
Hexahydropyrrolo simultaneously [3,4-b] oxazines base,
Dihydro phthalazinyl,
Diazabicyclo heptane base,
1,8- diaza spiro [4.5] decyl, and
5- oxa- -2- azaspiro [3.4] octyl,
All of which is optionally replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Oxo,
- OH,
- CN,
-CH3,
-CH2OH,
Methoxyl group,
-CH2CH3,
-C(O)CH3,
-C(O)NH2,
-OCH2CH2OH,
-OCH2CH2NH2,
-ONHC(NH)NH2,
-OC(O)NH2,
- O oxetanyl,
-CH2CH2OH,
-CH2CH2CH2OH,
-CH2CH2CH3,
-CH2CH2OCH3,
-CH2CH(OH)CH3,
-CH2CH(OH)CH2OH,
-CH2C(O)OCH3,
-CH2C(O)NH2,
-C(O)CH(CH3)2,
-CH2CH2N(CH3)2,
-CH2CH2NHCH2CH3,
-CH2CH2CH2N(CH3)2,
-CH2CH2NHCH2C(CH3)3,
-CH2CH2N(CH3)CH2OCH3,
-C(CH3)2CH2OH,
-CH2C(CH3)2OH,
-CH2C(CH3)2OCH3,
-C(O)CH2OH,
-CH2Isothiazolyl,
-CH2Thiazolyl,
-CH2Pyrazolyl,
-CH2Imidazole radicals,
-CH2Pyridyl group,
-CH2Oxazolyl,
-CH2Pyrrole radicals,
-CH2Isoxazolyl,
-CH2Furyl,
-CH2CH2Morpholinyl,
-CH2CH2Pyrrolidinyl,
-CH2CH2Pyrrolidinyl CH3,
-CH2CH2CH2Pyrrolidinyl,
- C (O) phenyl,
- C (O) C (THP trtrahydropyranyl) NH2,
-NH2,
-NHCH3,
-N(CH3)2,
-NHC(O)CH3,
-NHCH2CHF2,
-NHCH2C(CH3)3,
-NHCH2CH(CH3)2,
-NHCH2CH2OCH3,
-NHCH2CH2OH,
-NHCH2CH2NH2,
-NHCH2C (O) OH,
-NHC(O)CH2NH2,
-NHC(O)CH2CH2CH2NH2,
-NHCH2C(O)NH2,
-NHCH2C(OH)(CH3)2,
-NHC(O)CH(CH3)NH2,
-NHC(O)OCH(CH3)NH2,
-NHC(O)CH(CH3)2,
-NHC(O)C(CH3)2NH2,
-NHC(O)CH2OH,
-NHC(O)CH(CH2OH)NH2,
- NHC (O) (oxetanyl) NH2,
-NHC(O)OC(CH3)3,
-NHC(CH3)2C(O)OCH3,
- NH cyclopropyl,
- NH oxetanyl,
-CH2NH2,
-CH2CH2NH2,
-CH2CH2CH2NH2,
-CH2NHCH2C(CH3)3,
-CH2NHC(O)C(CH3)3,
-CH2NHC(O)CH2NH2,
-CH2NHC(O)CH2OH,
-CH2N(CH3)2,
-CH2NHCH3,
-CH2N(CH2CH3)2,
-CH2CH2N(CH3)2,
-S(O)2CH2CH3,
-S(O)2CH2CH2CH3,
-S(O)2Phenyl,
-S(O)2CH3,
Benzoyl,
Benzylamino,
3- pyrrolidinylpropyl,
2- Cvclopropvlmethvl,
Cyclobutylamino,
Cyclobutyl-N (CH3)-,
Piperidyl,
Imidazole radicals,
Morpholinyl,
Morpholinyl methyl,
Methyl piperazine ylmethyl,
Methyl piperazine base,
Pyrrolidinyl,
Pyrrolidinylmethyl,
Methoxypyridylmethyl amino,
Methylpyrrole alkyl,
Difluoropyrrolidin base,
Alkyl dimethyl pyrrole,
Methylcyclopropylmethyl amino,
Hydroxymethyl-pyrrolidine base,
Fluoropyrrolidine base,
Fluorophenyl methyl amino,
Piperizinylmethyl,
Oxazolidinyl,
Methy oxetane vlmethyl,
Methyl-cyclobutyl methylamino,
Oxoimidazolidinyl, and
2- hydroxyethylpiperidine base；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, in formula (Qb2) compound, R71c”For phenyl.
Suitably, in formula (Qb2) compound, the compound is the form of phosphate prodrugs.
Suitably, in formula (Qb2) compound, the compound is-C (O) CH (NH2)CH(CH3)2The form of prodrug.
Non- primary amide:
The present invention relates to the purposes of formula (Icr) compound and formula (Icr) compound in the methods of the invention:
Wherein:
X1crAnd X2crIndependently selected from:
Hydrogen,
Cyano,
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
Re,
-OC1-6Alkyl,
-ORe,
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocycle,
By RdReplace 1-4 heterocycle,
- SH, and
-SRa；
YcrIt is selected from: S, NH, NRz, O, S (O) and S (O)2；
R1crIt is selected from:
Amino,
-NHRa,
-NRbRc,
Cyano,
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
Re,
-OC1-6Alkyl,
-ORe,
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocycle,
By RdReplace 1-4 heterocycle,
Aryl,
By RdReplace 1-4 aryl,
Heteroaryl,
By RdReplace 1-4 heteroaryl,
- SH, and
-SRa；
R2crIt is selected from:
Hydrogen,
C1-6Alkyl, and
The C replaced by 1-6 substituent groups independently selected from the following1-6Alkyl:
Halogen ,-OH ,-COOH；
R3crIt is selected from:
Aryl,
By RdReplace 1-4 aryl,
Heteroaryl, and
By RdReplace 1-4 heteroaryl；
R4crIt is selected from:
Hydrogen,
C1-6Alkyl, and
The C replaced by 1-6 substituent groups independently selected from the following1-6Alkyl:
Halogen ,-OH ,-COOH；
R5crIt is selected from:
Amino,
-NHRa,
-NRbRc,
Aryl,
By RdReplace 1-4 aryl,
-C1-6Alkyl,
-OC1-6Alkyl,
-ORe,
- O aryl,
By RdReplace 1-4-O aryl,
- O heteroaryl,
By RdReplace 1-4-O heteroaryl,
- SH, and
-SRa；
Wherein:
Each RaIndependently selected from
C1-6Alkyl,
Re,
Aryl,
By RdReplace 1-4 aryl,
Heteroaryl,
By RdReplace 1-4 heteroaryl,
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl, and
By RdReplace 1-4 Heterocyclylalkyl；
RbAnd RcIndependently selected from:
C1-6Alkyl,
Re,
Aryl,
By RdReplace 1-4 aryl,
Heteroaryl,
By RdReplace 1-4 heteroaryl；
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl, and
By RdReplace 1-4 Heterocyclylalkyl, or
RbAnd RcNitrogen connected to them and the optional 1-3 additional hetero atoms independently selected from O, N and S are together Heterocyclylalkyl is formed, is optionally replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
Re,
-ORe,
Aryl,
By RdReplace 1-4 aryl,
Heteroaryl,
By RdReplace 1-4 heteroaryl,
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl, and
By RdReplace 1-4 Heterocyclylalkyl,
C1-4Alkoxy,
- CN,
Oxo,
- OH,
- COOH,
-NO2,
-NH2,
-N(H)C1-5Alkyl,
-N(H)Re,
-N(C1-5Alkyl)2,
-NReRe,
-N(Re)C1-5Alkyl,
-ONHC(NH)NH2,
- O Heterocyclylalkyl,
- NH naphthenic base,
-N(C1-5Alkyl) naphthenic base,
- NH Heterocyclylalkyl,
-N(C1-5Alkyl) Heterocyclylalkyl,
-S(O)2C1-4Alkyl,
-SO2NH2
-S(O)2Phenyl,
Benzoyl,
2- methylcyclopropyl groups,
Imidazole radicals,
(methoxypyridylmethyl) amino,
(methylcyclopropylmethyl) amino,
(fluorophenyl methyl) amino,
(methy oxetane ylmethyl) amino, and
(methyl-cyclobutyl methyl) amino；
Each RdIndependently selected from:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
Re,
Heteroaryl,
By RxReplace 1-4 heteroaryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Naphthenic base,
By RxReplace 1-4 naphthenic base,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Heterocyclylalkyl,
By RxReplace 1-4 Heterocyclylalkyl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, fluorine, oxo, C1-6Alkyl and by 1-6 independently The C that substituent group selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Aryl,
By RxReplace 1-4 aryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
C1-4Alkoxy,
The C replaced by 1-4 substituent groups independently selected from the following1-4Alkoxy: fluorine, oxo ,-OH ,-COOH ,-NH2、- NHC1-4Alkyl ,-N (C1-4Alkyl)2With-CN,
- O aryl,
By RxReplace 1-4-O aryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-ORe,
- C (O) H,
-C(O)Rzz,
- C (O) aryl,
By RzzFor 1-4-C (O) aryl,
- C (O) heteroaryl,
By RzzFor 1-4-C (O) heteroaryl,
- OC (O) H,
-CO(O)Rzz,
- OC (O) aryl,
By RzzFor 1-4-CO (O) aryl,
- OC (O) heteroaryl,
By RzzFor 1-4-OC (O) heteroaryl,
Sulfydryl,
-SRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- S (O) H,
-S(O)Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2H,
-S(O)2Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-OS(O)2Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2NH2,
-S(O)2NHRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl, and by 1-6 The C that a substituent group independently selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-P(O)(CH3)2,
-NHS(O)2H,
-NHS(O)2Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- NHC (O) H,
-NHC(O)Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-C(O)NH2,
-C(O)NHRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-C(O)NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 The C that substituent group independently selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- C (O) OH,
-C(O)ORx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Oxo,
Hydroxyl,
Amino,
-NHRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl, by 1-6 independently selected from fluorine, oxygen Generation ,-OH ,-COOH ,-NH2The C replaced with the substituent group of-CN1-6Alkyl, C1-6Alkoxy and by 1-6 independently selected from following Substituent group replace C1-6Alkoxy: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN
-NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl ,-S (O)2C1-6Alkyl, quilt 1-6 independently selected from fluorine, oxo ,-OH ,-COOH ,-NH2- the S (O) replaced with the substituent group of-CN2C1-6Alkyl, C1-6Alkyl With the C replaced by 1-6 substituent groups independently selected from the following1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Boric acid,
Nitro,
Cyano,
-NHC(O)NH2,
-NHC(O)NHRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-NHC(O)NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 The C that substituent group independently selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Each ReIndependently selected from:
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Fluorine,
Chlorine,
Bromine,
Iodine,
-OC1-6Alkyl,
- the OC replaced by 1-6 substituent groups independently selected from the following1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2 With-CN,
-OC(O)C1-6Alkyl,
- OC (O) C replaced by 1-6 substituent groups independently selected from the following1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,- NH2With-CN,
-ONHC(NH)NH2,
-OP(O)(OH)2,
Sulfydryl,
-SRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- S (O) H,
-S(O)Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2H,
-S(O)2Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Oxo,
Hydroxyl,
Amino,
-NHRxx,
Wherein RxxSelected from aryl, heteroaryl, naphthenic base, by C1-4The naphthenic base of alkoxy substitution is independently selected by 1-6 The C replaced from substituent group below1-4Alkoxy: fluorine, triazolyl, cyclopropyl, oxo ,-ORxy,-COOH ,-CN and-NRxyRxz,
Wherein RxyAnd RxzIndependently selected from: hydrogen, aryl, C1-5Alkyl cycloheteroalkyl, C1-6Alkyl and by 1-6 independently The C that substituent group selected from the following replaces1-6Alkyl: fluorine, oxo ,-ORxy,-COOH ,-CN and-NRxyRxz, wherein RxyAnd RxzIt is independent Ground is selected from: hydrogen, aryl, C1-5Alkyl and the C replaced by 1-4 substituent groups independently selected from the following1-5Alkyl: fluorine, triazolyl, Cyclopropyl, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
-NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 The C that substituent group independently selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Guanidine radicals,
- C (O) OH,
-C(O)ORx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-C(O)NH2,
-C(O)NHRx,
Wherein RxSelected from aryl, heteroaryl ,-OH, C1-4Alkoxy, naphthenic base, by HO- (C1-4Alkyl)-replace cycloalkanes Base, Heterocyclylalkyl, by HO- (C1-4Alkyl)-replace Heterocyclylalkyl, C1-6It alkyl and is taken by 1-6 is independently selected from the following The C replaced for base1-6Alkyl: fluorine, oxo ,-OH ,-COOH, heteroaryl ,-NH2With-CN,
-C(O)NRx1Rx2,
Wherein Rx1And Rx2Be each independently selected from aryl, heteroaryl, naphthenic base, by HO- (C1-4Alkyl)-replace cycloalkanes Base, Heterocyclylalkyl, C1-6Alkyl and the C replaced by 1-6 substituent groups independently selected from the following1-6Alkyl: fluorine, oxo ,-OH ,- COOH、-NH2With-CN,
Or Rx1And Rx2Nitrogen connected to them and the optional 1-3 additional hetero atoms independently selected from O, N and S It is formed together Heterocyclylalkyl, is optionally replaced by 1-5 substituent groups independently selected from the following: fluorine, oxo ,-OH, HO- (C1-4 Alkyl)-,-COOH ,-NH2With-CN,
Aryl,
By RxReplace 1-4 aryl,
Wherein RxSelected from fluorine, chlorine, bromine, iodine, aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 solely The on the spot C that substituent group selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2、N(CH3)2、-NHC(O)C1-4Alkane Base and-CN,
- O aryl,
By RxReplace 1-4-O aryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Heteroaryl,
By RxReplace 1-4 heteroaryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-4Alkoxy, C1-6Alkyl and independent by 1-6 The C that ground substituent group selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- O heteroaryl,
By RxReplace 1-4-O heteroaryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Naphthenic base,
By RxReplace 1-4 naphthenic base,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Heterocyclylalkyl,
By RxReplace 1-4 Heterocyclylalkyl,
Wherein RxSelected from oxo ,-OH ,-N (C1-4Alkyl)2, aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and The C replaced by 1-6 substituent groups independently selected from the following1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2,-N (CH3)2With- CN,
-S(O)2NH2,
-S(O)2NHRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 The C that substituent group independently selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-NHS(O)2H,
-NHS(O)2Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-OC(O)NH2,
-NHC(O)Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN
-NHC(O)NHRxp,
Wherein RxpReplaced selected from heteroaryl, naphthenic base, Heterocyclylalkyl and by 1-4 substituent groups independently selected from the following C1-6Alkyl :-COOH ,-NH2With-CN,
-NHC(O)NRx3Rx4,
Wherein Rx3And Rx4Be each independently selected from heteroaryl, naphthenic base, Heterocyclylalkyl and by 1-6 independently selected from Under substituent group replace C1-6Alkyl :-COOH ,-NH2With-CN,
-NHC(O)C(O)NH2,
-NO2With
-CN；With
RzIt is selected from
C1-6Alkyl,
Re,
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl, and
By RdReplace 1-4 Heterocyclylalkyl；With
RzzIt is selected from
C1-6Alkyl, and
Re；
On condition that:
X1crAnd X2crIt is not all hydrogen；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, in formula (Icr) compound, X1crAnd X2crIt is not hydrogen.
Suitably, in formula (Icr) compound, the compound is the form of phosphate prodrugs.
Suitably, in formula (Icr) compound, the compound is-C (O) CH (NH2)CH(CH3)2The form of prodrug.
What it is included in the compounds of this invention and for the method for the present invention is formula (IIcr) compound:
Wherein:
X21crAnd X22crIndependently selected from:
Hydrogen,
Cyano,
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
Re,
-OC1-6Alkyl,
-ORe,
Naphthenic base,
Heterocycle, and
-SH；
Y1crIt is selected from: S, NH and NRz；
R21crIt is selected from:
Amino,
Cyano,
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
Re,
-OC1-6Alkyl,
-ORe,
-NHRa,
-NRbRc,
Aryl,
By RdReplace 1-4 aryl,
Heteroaryl,
By RdReplace 1-4 heteroaryl,
Naphthenic base,
By RdThe naphthenic base of substituted 1-4 times,
Heterocycle,
By RdThe heterocycle of substituted 1-4 times,
- SH, and
-SRa；
R22crIt is selected from:
Hydrogen,
C1-6Alkyl, and
The C replaced by 1-6 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine and bromine；
R23crIt is selected from:
Aryl,
By RdReplace 1-4 aryl,
Heteroaryl, and
By RdReplace 1-4 heteroaryl；
R24crIt is selected from:
Hydrogen,
C1-6Alkyl, and
The C replaced by 1-6 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine and bromine；
R25crIt is selected from:
Amino,
-NHRa,
-NRbRc,
Aryl,
By RdReplace 1-4 aryl,
-OC1-6Alkyl,
-ORe,
- O aryl,
- O heteroaryl,
- SH, and
-SRa；
Wherein:
Each RaIndependently selected from
C1-6Alkyl,
Re,
Aryl,
By RdReplace 1-4 aryl,
Heteroaryl,
By RdReplace 1-4 heteroaryl,
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl, and
By RdReplace 1-4 Heterocyclylalkyl；
RbAnd RcIndependently selected from:
C1-6Alkyl,
Re,
Aryl,
By RdReplace 1-4 aryl,
Heteroaryl,
By RdReplace 1-4 heteroaryl；
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl, and
By RdReplace 1-4 Heterocyclylalkyl, or
RbAnd RcNitrogen connected to them and optional 1-3 additional hetero atoms are formed together Heterocyclylalkyl, optionally Replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
Re,
-ORe,
Aryl,
By RdReplace 1-4 aryl,
Heteroaryl,
By RdReplace 1-4 heteroaryl,
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl, and
By RdReplace 1-4 Heterocyclylalkyl,
C1-4Alkoxy,
The C replaced by 1-6 substituent groups independently selected from the following1-4Alkoxy: fluorine, oxo ,-OH ,-COOH ,-NH2 With-CN,
- CN,
Oxo,
- OH,
- COOH,
-NO2,
-NH2,
-N(H)C1-4Alkyl,
-N(H)Re,
-N(C1-4Alkyl)2,
-ONHC(NH)NH2,
- O Heterocyclylalkyl,
- NH naphthenic base,
- NH Heterocyclylalkyl,
-S(O)2CH2CH3,
-S(O)2CH2CH2CH3,
-S(O)2Phenyl,
-S(O)2CH3,
Benzoyl,
Benzylamino,
3- pyrrolidinylpropyl,
2- Cvclopropvlmethvl,
Cyclobutylamino,
Cyclobutyl-N (CH3)-,
Piperidyl,
Imidazole radicals,
Morpholinyl,
Morpholinyl methyl,
Methyl piperazine ylmethyl,
Methyl piperazine base,
Pyrrolidinyl,
Pyrrolidinylmethyl,
Methoxypyridylmethyl amino,
Methylpyrrole alkyl,
Difluoropyrrolidin base,
Alkyl dimethyl pyrrole,
Methylcyclopropylmethyl amino,
Hydroxymethyl-pyrrolidine base,
Fluoropyrrolidine base,
Fluorophenyl methyl amino,
Piperizinylmethyl,
Oxazolidinyl,
Methy oxetane vlmethyl,
Methyl-cyclobutyl methylamino,
Oxoimidazolidinyl and
2- hydroxyethylpiperidine base；
Each RdIndependently selected from:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
Re,
Heteroaryl,
By RxReplace 1-4 heteroaryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Naphthenic base,
By RxReplace 1-4 naphthenic base,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Heterocyclylalkyl,
By RxReplace 1-4 Heterocyclylalkyl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, fluorine, oxo, C1-6Alkyl and by 1-6 independently The C that substituent group selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Aryl,
By RxReplace 1-4 aryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
C1-4Alkoxy,
The C replaced by 1-4 substituent groups independently selected from the following1-4Alkoxy:
Fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- O aryl,
By RxReplace 1-4-O aryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- C (O) H,
-C(O)Rzz,
- C (O) aryl,
By RzzFor 1-4-C (O) aryl,
- C (O) heteroaryl,
By RzzFor 1-4-C (O) heteroaryl,
- OC (O) H,
-CO(O)Rzz,
- OC (O) aryl,
By RzzFor 1-4-CO (O) aryl,
- OC (O) heteroaryl,
By RzzFor 1-4-OC (O) heteroaryl,
Sulfydryl,
-SRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- S (O) H,
-S(O)Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2H,
-S(O)2Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-OS(O)2Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2NH2,
-S(O)2NHRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 The C that substituent group independently selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-NHS(O)2H,
-NHS(O)2Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- NHC (O) H,
-NHC(O)Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-C(O)NH2,
-C(O)NHRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-C(O)NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 The C that substituent group independently selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- C (O) OH,
-C(O)ORx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Oxo,
Hydroxyl,
Amino,
-NHRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl ,-S (O)2C1-6Alkyl, quilt 1-6 independently selected from fluorine, oxo ,-OH ,-COOH ,-NH2- the S (O) replaced with the substituent group of-CN2C1-6Alkyl, C1-6Alkyl With the C replaced by 1-6 substituent groups independently selected from the following1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Boric acid,
Nitro,
Cyano,
-NHC(O)NH2,
-NHC(O)NHRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-NHC(O)NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 The C that substituent group independently selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Each ReIndependently selected from:
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
-OC1-6Alkyl,
- the OC replaced by 1-6 substituent groups independently selected from the following1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2 With-CN,
Sulfydryl,
-SRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- S (O) H,
-S(O)Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2H,
-S(O)2Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Oxo,
Hydroxyl,
Amino,
-NHRxx,
Wherein RxxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-ORxy、-COOH、-CN、-OC1-5Alkyl, by fluorine and-NRxyRxzReplace 1-6 times - OC1-5Alkyl, wherein RxyAnd RxzIndependently selected from: hydrogen, aryl, C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
-NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 The C that substituent group independently selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN, guanidine radicals,
- C (O) OH,
-C(O)ORx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-C(O)NH2,
-C(O)NHRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-C(O)NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 The C that substituent group independently selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Aryl,
By RxReplace 1-4 aryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- O aryl,
By RxReplace 1-4-O aryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Heteroaryl,
By RxReplace 1-4 heteroaryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- O heteroaryl,
By RxReplace 1-4-O heteroaryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Naphthenic base,
By RxReplace 1-4 naphthenic base,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Heterocyclylalkyl,
By RxReplace 1-4 Heterocyclylalkyl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2NH2,
-S(O)2NHRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 The C that substituent group independently selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-NHS(O)2H,
-NHS(O)2Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-NHC(O)NHRxp,
Wherein RxpReplaced selected from heteroaryl, naphthenic base, Heterocyclylalkyl and by 1-4 substituent groups independently selected from the following C1-6Alkyl :-COOH ,-NH2With-CN,
-NHC(O)NRx3Rx4,
Wherein Rx3And Rx4Be each independently selected from heteroaryl, naphthenic base, Heterocyclylalkyl and by 1-6 independently selected from Under substituent group replace C1-6Alkyl :-COOH ,-NH2With-CN,
Nitro and
Cyano；
RzIt is selected from
C1-6Alkyl,
Re,
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl, and
By RdReplace 1-4 Heterocyclylalkyl；
RzzIt is selected from
C1-6Alkyl, and
Re；
On condition that:
X21crAnd X22crIt is not all hydrogen；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, in formula (IIcr) compound, X21crAnd X22crIt is not hydrogen.
Suitably, in formula (IIcr) compound, the compound is the form of phosphate prodrugs.
Suitably, in formula (IIcr) compound, the compound is-C (O) CH (NH2)CH(CH3)2The form of prodrug.
What it is included in the compounds of this invention and for the method for the present invention is formula (IIIcr) compound:
Wherein:
X31crAnd X32crIndependently selected from:
Hydrogen,
Cyano,
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
-OC1-6Alkyl,
Naphthenic base, and
-SH；
Y2crIt is selected from: S, NH and NRz；
R31crIt is selected from:
C1-6Alkyl,
Re1,
-OC1-6Alkyl,
-ORe1,
-NHRa1,
-NRb1Rc1,
Aryl,
By Rd1Replace 1-4 aryl,
Heteroaryl,
By Rd1Replace 1-4 heteroaryl,
Naphthenic base,
By Rd1Replace 1-4 naphthenic base,
Heterocyclylalkyl,
By Rd1Replace 1-4 Heterocyclylalkyl,
- SH, and
-SRa1；
R32crIt is selected from:
Hydrogen,
C1-3Alkyl, and
Replaced 1-4 C by fluorine1-3Alkyl；
R33crIt is selected from:
Aryl,
By Rd1Replace 1-4 aryl,
Heteroaryl, and
By Rd1Replace 1-4 heteroaryl；
R34crIt is selected from:
Hydrogen,
C1-3Alkyl, and
Replaced 1-4 C by fluorine1-3Alkyl；
R35crIt is selected from:
Amino,
-NHRa1,
-NRb1Rc1,
Aryl,
By Rd1Replace 1-4 aryl,
-OC1-6Alkyl,
-ORe1,
- SH, and
-SRa1；
Wherein:
Each Ra1Independently selected from
C1-6Alkyl,
Re1,
Aryl,
Heteroaryl,
Naphthenic base,
Heterocyclylalkyl, and
By Rd1Replace 1-4 Heterocyclylalkyl；
Rb1And Rc1Independently selected from:
C1-6Alkyl,
Re1,
-ORe1,
Aryl,
By Rd1Replace 1-4 aryl,
Heteroaryl,
By Rd1Replace 1-4 heteroaryl；
Naphthenic base,
By Rd1Replace 1-4 naphthenic base,
Heterocyclylalkyl, and
By Rd1Replace 1-4 Heterocyclylalkyl, or
Rb1And Rc1Nitrogen connected to them and optional 1-3 additional hetero atoms are formed together Heterocyclylalkyl, times Choosing is replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
Re1,
Aryl,
By Rd1Replace 1-4 aryl,
Naphthenic base,
By Rd1Replace 1-4 naphthenic base,
Heterocyclylalkyl, and
By Rd1Replace 1-4 Heterocyclylalkyl,
C1-4Alkoxy,
The C replaced by 1-6 substituent groups independently selected from the following1-4Alkoxy: fluorine, oxo ,-OH ,-COOH ,-NH2 With-CN,
- CN,
Oxo,
- OH,
- COOH,
-NO2,
-NH2,
-N(H)C1-4Alkyl,
-N(H)Re1,
-N(C1-4Alkyl)2,
-ONHC(NH)NH2,
- O Heterocyclylalkyl,
- NH naphthenic base,
- NH Heterocyclylalkyl,
-S(O)2CH2CH3,
-S(O)2CH2CH2CH3,
-S(O)2Phenyl,
-S(O)2CH3,
Benzoyl,
Benzylamino,
3- pyrrolidinylpropyl,
2- Cvclopropvlmethvl,
Cyclobutylamino,
Cyclobutyl-N (CH3)-,
Piperidyl,
Imidazole radicals,
Morpholinyl,
Morpholinyl methyl,
Methyl piperazine ylmethyl,
Methyl piperazine base,
Pyrrolidinyl,
Pyrrolidinylmethyl,
Methoxypyridylmethyl amino,
Methylpyrrole alkyl,
Difluoropyrrolidin base,
Alkyl dimethyl pyrrole,
Methylcyclopropylmethyl amino,
Hydroxymethyl-pyrrolidine base,
Fluoropyrrolidine base,
Fluorophenyl methyl amino,
Piperizinylmethyl,
Oxazolidinyl,
Methy oxetane vlmethyl,
Methyl-cyclobutyl methylamino,
Oxoimidazolidinyl and
2- hydroxyethylpiperidine base；
Each Rd1Independently selected from:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
Re1,
Heteroaryl,
By RxaReplace 1-4 heteroaryl,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
Naphthenic base,
By RxaReplace 1-4 naphthenic base,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
Heterocyclylalkyl,
By RxReplace 1-4 Heterocyclylalkyl,
Wherein RxIt is selected from: fluorine, oxo, C1-6Alkyl and the C replaced by 1-6 substituent groups independently selected from the following1-6Alkane Base: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Aryl,
By RxaReplace 1-4 aryl,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base, C1-4Alkoxy,
The C replaced by 1-4 substituent groups independently selected from the following1-4Alkoxy: fluorine and-NH2,
- O aryl,
- C (O) H,
-C(O)Rzz,
- C (O) aryl,
- C (O) heteroaryl,
- OC (O) H,
-CO(O)Rzz,
- OC (O) aryl,
- OC (O) heteroaryl,
Sulfydryl,
-SRxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
- S (O) H,
-S(O)Rxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
-S(O)2H,
-S(O)2Rxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
-OS(O)2Rxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
-S(O)2NH2,
-S(O)2NHRxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
-NHS(O)2H,
-NHS(O)2Rxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
- NHC (O) H,
-NHC(O)Rxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
-C(O)NH2,
-C(O)NHRxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
- C (O) OH,
-C(O)ORxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
Oxo,
Hydroxyl,
Amino,
-NRx1aRx2a,
Wherein Rx1aAnd Rx2aIt is each independently selected from-S (O)2C1-6Alkyl and C1-6Alkyl,
-NHRxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
Nitro,
Cyano,
Boric acid,
-NHC(O)NH2, and
-NHC(O)NHRxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base；
Each Re1Independently selected from:
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
-OC1-6Alkyl,
- the OC replaced by 1-6 substituent groups independently selected from the following1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2 With-CN,
Sulfydryl,
-SRxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
- S (O) H,
-S(O)Rxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
-S(O)2H,
-S(O)2Rxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
Oxo,
Hydroxyl,
Amino,
-NHRxx,
Wherein RxxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-ORxy、-COOH、-CN、-OC1-5Alkyl, by fluorine and-NRxyRxzReplace 1-6 times - OC1-5Alkyl, wherein RxyAnd RxzIndependently selected from: hydrogen, aryl, C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
-NRx1xRx2x,
Wherein Rx1xAnd Rx2xIt is each independently selected from C1-4Alkyl and replaced by 1-4 substituent groups independently selected from the following C1-4Alkyl: fluorine, oxo and-OH,
Guanidine radicals,
- C (O) OH,
-C(O)ORxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
-C(O)NHRxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base and Heterocyclylalkyl,
Aryl,
By RxaReplace 1-4 aryl,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
- O aryl,
By RxaReplace 1-4-O aryl,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
Heteroaryl,
By RxaReplace 1-4 heteroaryl,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
- O heteroaryl,
By RxaReplace 1-4-O heteroaryl,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
Naphthenic base,
By RxReplace 1-4 naphthenic base,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Heterocyclylalkyl,
By RxReplace 1-4 Heterocyclylalkyl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 independently selected from following Substituent group replace C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2NH2,
-S(O)2NHRxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
-NHS(O)2H,
-NHS(O)2Rxa,
Wherein RxaSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and replaced 1-6 C by fluorine1-6Alkane Base,
-NHC(O)NHRxa,
Wherein RxaSelected from heteroaryl, naphthenic base and Heterocyclylalkyl,
Nitro and
Cyano；
RzIt is selected from
C1-6Alkyl,
Re1,
Naphthenic base,
By Rd1Replace 1-4 naphthenic base,
Heterocyclylalkyl, and
By Rd1Replace 1-4 Heterocyclylalkyl；
RzzIt is selected from
C1-6Alkyl, and
Re1；
On condition that:
X31crAnd X32crIt is not all hydrogen；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, in formula (IIIcr) compound, X31crAnd X32crIt is not hydrogen.
Suitably, in formula (IIIcr) compound, the compound is the form of phosphate prodrugs.
Suitably, in formula (IIIcr) compound, the compound is-C (O) CH (NH2)CH(CH3)2The form of prodrug.
The present invention relates to the purposes of new formula (IVccr) compound and formula (IVccr) compound in the methods of the invention:
Wherein:
X41ccrAnd X42ccrIndependently selected from :-CN, methyl, fluorine, chlorine, bromine and iodine；
Y4ccrIt is selected from: S and NH；
R41ccrIt is selected from:
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo, C1-4Alkyl oxygen Base ,-OH ,-COOH ,-NH2-N(H)C1-4Alkyl ,-N (C1-4Alkyl)2With-CN,
C1-4Alkyl oxy,
Replaced 1-4 C by fluorine1-4Alkyl oxy,
-N(H)C1-4Alkyl,
-N(C1-4Alkyl)2,
-SC1-4Alkyl,
Aryl,
The aryl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-OH ,-NH2 With-CN,
C1-4Alkoxy,
- CN,
Oxo,
- OH,
-NO2, and
-NH2,
Heteroaryl,
The heteroaryl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-OH ,-NH2 With-CN,
C1-4Alkoxy,
- CN,
Oxo,
- OH,
-NO2, and
-NH2,
Naphthenic base,
The naphthenic base replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-OH ,-NH2 With-CN,
C1-4Alkoxy,
- CN,
Oxo,
- OH,
-NO2, and
-NH2；
R43ccrIt is selected from:
Aryl,
The aryl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-4Alkoxy,
The C replaced by 1-3 substituent groups independently selected from the following1-4Alkoxy: fluorine, chlorine, oxo ,-OH ,-NH2,- NHCH3With-N (CH3)2,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-S (O)2C1-4 Alkyl ,-CN ,-OR49With-NR46R47,
Wherein R46And R47Independently selected from: hydrogen ,-S (O)2CH3, pyrazoles, C1-5Alkyl and by 1-4 independently selected from following Substituent group replace C1-5Alkyl:
Fluorine, oxo ,-OH ,-OC1-5Alkyl, and by fluorine ,-COOH and-NR48R49Replace 1-6-OC1-5Alkyl, Middle R48And R49Independently selected from: hydrogen, phenyl, C1-5Alkyl and the C replaced by 1-4 substituent groups independently selected from the following1-5Alkane Base: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
- CN,
Oxo,
- OH,
Heterocyclylalkyl,
It is independently selected from the Heterocyclylalkyl of substituent group substitution below once or twice: fluorine and oxo,
-N(CH3)S(O)2CFH2,
-N(CH3)S(O)2CF2H,
-N(CH3)S(O)2CF3,
-OS(O)2CH3,
-S(O)2NH2,
-S(O)2NHCH3,
–NR80a’R81a’, wherein R80a’And R81a’Independently selected from: hydrogen ,-S (O)2CH3, phenyl, C1-5Alkyl and by 1-4 The C that substituent group independently selected from the following replaces1-5Alkyl: fluorine, oxo ,-OH ,-NH2、-OC1-5Alkyl is taken by fluorine and-COOH For 1-6-OC1-5Alkyl,
Boric acid,
-NO2, and
-NH2,
Heteroaryl, and
The heteroaryl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-CN ,-OR49 With-NR46R47,
Wherein R46And R47Independently selected from: hydrogen ,-S (O)2CH3、C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR48R49Replace 1-6-OC1-5Alkane Base, wherein R48And R49Independently selected from: hydrogen, phenyl, C1-5Alkyl and replaced by 1-4 substituent groups independently selected from the following C1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
C1-4Alkoxy,
- CN,
Oxo,
- OH,
-S(O)2NH2,
-S(O)2NHCH3,
-NO2, and
-NH2；With
R44ccrAnd R45ccrIndependently selected from:
Hydrogen,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Phenyl, morpholino, triazolyl, imidazole radicals, pyrrolidinyl ,-OC (O) NH2、-OCH2CH2NH2、-ONHC(NH2) NH2、-NHCH2C(CH3)3、-NOCH3、-NHOH、-NHCH2CH2F、-N(CH3)CH2CH2OCH3、-N(CH2CH3)2、-NCH (CH2OH)2、-N(CH2CH2OH)2、-NHCH2CH2OH、-NHCH2CH2NH2、-N(CH3)C(CH3)2CH2OH、-NHCH2CH3、- NHCH2CH2OCH3、-N(CH3)CH2CH2OH、-NHC(O)C(O)NH2、-N(CH3)CH2CH2CH2OH、-N(CH3)CH2CH(OH) CH2OH、-N(CH3)CH2CH2NH2, oxo ,-NHCH2C(CH3)2CH2OH、-OH、-NH2、-NHCH3、-NHCH2CH2CH2OH、-N (CH3)2、-N(CH3)CH2CH3、-NHOC(CH3)2NH2、-N(CH3)CH2Cyclopropyl ,-NHCH2Cyclopropyl ,-NH oxetanes Base ,-NCH2CH2Triazole, piperazinyl, piperidyl, pyrazolyl, azepine cycloheptatriene base, azetidinyl, methoxyl group and cyclopropyl Base amino,
The wherein phenyl, morpholino, triazolyl, imidazole radicals, azepine cycloheptatriene base, azetidinyl, pyrrolidines Base, piperazinyl, piperidyl, oxetanyl, cyclopropyl and pyrazolyl are optionally by 1-4 substituent groups independently selected from the following Replace: methyl, fluorine ,-NH2、-N(CH3)2, hydroxymethyl, oxo ,-OH and-CH2NH2,
Naphthenic base,
The naphthenic base replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH,
C1-6Alkyl, and
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine and chlorine；
Heterocyclylalkyl and
The Heterocyclylalkyl replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-OH ,-NH2 With-CN,
Aryl,
C1-4Alkoxy,
The C replaced by 1-4 substituent groups independently selected from the following1-4Alkoxy: fluorine, oxo ,-OH ,-COOH ,-NH2 With-CN,
- CN,
Oxo,
- OH,
- COOH,
-NO2,
-NH2, and
SO2NH2, or
R44ccrAnd R45ccrNitrogen connected to them and the optional 1-3 additional miscellaneous originals independently selected from O, N and S Son is formed together Heterocyclylalkyl, is optionally replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, C1-4Alkoxy, oxo, phenyl, Naphthenic base, Heterocyclylalkyl, methyl heterocycles alkyl-,-OH ,-NH2、-N(H)C1-5Alkyl, amino-heterocycles alkyl-,-N (C1-5Alkyl )2、-CN、-N(C1-4Alkyl) (CH2OCH3) and-NHC that is replaced by 1 or 2 substituent group independently selected from the following1-4Alkyl: oxygen Generation, NH2With-OH,
Aryl,
Naphthenic base,
Heterocyclylalkyl,
The Heterocyclylalkyl replaced by 1-9 substituent groups independently selected from the following: C1-6Alkyl ,-C1-6Alkyl OH, fluorine ,- C1-6Alkyl NH2, chlorine, bromine, iodine, oxo ,-OH ,-NH2With-CN,
C1-4Alkoxy,
The C replaced by 1-4 substituent groups independently selected from the following1-4Alkoxy: fluorine, oxo ,-OH ,-COOH ,-NH2 With-CN,
- CN,
Oxo,
- OH,
-OP(O)(OH)2,
- COOH,
-NO2,
-NH2,
-N(H)C1-5Alkyl,
- N (H) C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Fluorine, chlorine, bromine, iodine, C1-4Alkoxy, oxo, phenyl, naphthenic base, amino C1-4Alkoxy, Heterocyclylalkyl, methyl are miscellaneous Naphthenic base ,-OH ,-NH2、-N(H)C1-4Alkyl ,-N (C1-4Alkyl)2With-CN,
- O oxetanyl,
-ONHC(NH)NH2,
- NH cyclopropyl,
- NH oxetanyl,
-N(C1-5Alkyl)2,
-S(O)2CH2CH3,
S(O)2CH2CH2CH3,
-S(O)2CH3,
-SO2NH2,
-S(O)2Phenyl,
Benzoyl,
Benzylamino,
Propylpyrrolidinyl,
Methylcyclopropyl groups,
Cyclobutylamino,
Cyclobutyl-N (CH3)-,
Piperidyl,
Imidazole radicals,
Morpholinyl,
Morpholinyl methyl,
Methyl piperazine ylmethyl,
Methyl piperazine base,
Pyrrolidinyl,
Pyrrolidinylmethyl,
(methoxypyridylmethyl) amino,
Methylpyrrole alkyl,
Difluoropyrrolidin base,
Alkyl dimethyl pyrrole,
(methylcyclopropylmethyl) amino,
Hydroxymethyl-pyrrolidine base,
Fluoropyrrolidine base,
Fluorophenyl methyl amino,
Piperizinylmethyl,
Oxazolidinyl,
(methy oxetane ylmethyl) amino,
(methyl-cyclobutyl methyl) amino,
Oxoimidazolidinyl, and
2- hydroxyethylpiperidine base；
On condition that:
R44ccrAnd R45ccrIt is not all hydrogen；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, in formula (IVccr) compound, the compound is the form of phosphate prodrugs.
Suitably, in formula (IVccr) compound, the compound is-C (O) CH (NH2)CH(CH3)2The form of prodrug.
Suitably, in formula (IVccr) compound, R44ccrAnd R45ccrIt is not hydrogen.
Suitably, in formula (IVccr) compound, R43ccrFor what is replaced by 1-4 substituent groups independently selected from the following Aryl:
Fluorine,
Chlorine,
Bromine,
Iodine,
Heterocyclylalkyl,
It is independently selected from the Heterocyclylalkyl that substituent group below replaces 1 or 2 time: fluorine and oxo,
-OS(O)2CH3,
-N(CH3)S(O)2CH3,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-S (O)2C1-4 Alkyl ,-CN ,-OR49With-NR46R47,
Wherein R46And R47Independently selected from: hydrogen ,-S (O)2CH3、C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR48R49Replace 1-6-OC1-5Alkane Base, wherein R48And R49Independently selected from: hydrogen, phenyl, C1-5Alkyl and replaced by 1-4 substituent groups independently selected from the following C1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl.
The present invention relates to the purposes of new formula (Vccr) compound and formula (Vccr) compound in the methods of the invention:
Wherein:
Y5ccrIt is selected from: S and NH；
R50ccrIt is selected from:
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine and chlorine,
-N(H)C1-4Alkyl,
-N(C1-4Alkyl)2,
-SC1-4Alkyl,
C1-4Alkyl oxy,
Aryl,
The aryl replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH,
C1-6Alkyl, and
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Fluorine and chlorine,
Heteroaryl,
The heteroaryl replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH,
C1-6Alkyl, and
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Fluorine and chlorine,
Naphthenic base,
The naphthenic base replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH,
C1-6Alkyl, and
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Fluorine and chlorine；
R52ccrIt is selected from:
Aryl,
The aryl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
C1-4Alkoxy,
The C replaced by 1-3 substituent groups independently selected from the following1-4Alkoxy: fluorine, chlorine, oxo ,-OH ,-NH2、- NHCH3With-N (CH3)2,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-S (O)2CH3、-CN、-OR59With-NR56R57,
Wherein R56And R57Independently selected from: hydrogen ,-S (O)2CH3、C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR58R59Replace 1-6-OC1-5Alkane Base, wherein R58And R59Independently selected from: hydrogen, phenyl, C1-5Alkyl and replaced by 1-4 substituent groups independently selected from the following C1-5
Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
Oxo,
- CN,
Tetrahydro isothiazolyl,
Tetrahydro isothiazolyl twice is replaced by oxo,
Tetrahydro -1,2-thiazines base,
Tetrahydro twice -1,2-thiazines base is replaced by oxo,
-N(CH3)S(O)2CH3,
-N(CH3)S(O)2CFH2,
-N(CH3)S(O)2CF2H,
-N(CH3)S(O)2CF3,
-OS(O)2CH3,
-S(O)2NH2,
-S(O)2NHCH3,
–NR80a’R81a’, wherein R80a’And R81a’Independently selected from: hydrogen ,-S (O)2CH3, phenyl, C1-5Alkyl and by 1-4 The C that substituent group independently selected from the following replaces1-5Alkyl: fluorine, oxo ,-OH ,-NH2、-OC1-5Alkyl is taken by fluorine and-COOH For 1-6-OC1-5Alkyl, and-OH；
Heteroaryl, and
The heteroaryl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-CN ,-OR59 With-NR56R57,
Wherein R56And R57Independently selected from: hydrogen ,-S (O)2CH3、C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR58R59Replace 1-6-OC1-5Alkane Base, wherein R58And R59Independently selected from: hydrogen, phenyl, C1-5Alkyl and replaced by 1-4 substituent groups independently selected from the following C1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
Oxo,
-S(O)2NH2,
-S(O)2NHCH3,
-OH；With
R53ccrAnd R54ccrIndependently selected from:
Hydrogen,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Phenyl, morpholino, triazolyl, imidazole radicals ,-CH2CH2Pyrrolidinyl ,-OC (O) NH2、-OCH2CH2NH2、-ONHC (NH2)NH2、-NHCH2C(CH3)3、-NOCH3、-NHOH、-NHCH2CH2F、-N(CH3)CH2CH2OCH3、-N(CH2CH3)2、-NCH (CH2OH)2、-N(CH2CH2OH)2、-NHCH2CH2OH、-NHCH2CH2NH2、-N(CH3)CH2(CH3)2CH2OH、-NHCH2CH3、- NHCH2CH2OCH3、-N(CH3)CH2CH2OH、-NHC(O)C(O)NH2、-N(CH3)CH2CH2CH2OH、-N(CH3)CH2CH(OH) CH2OH、-N(CH3)CH2CH2NH2, oxo ,-NHCH2C(CH3)2CH2OH、-OH、-NH2、-NHCH3、-NHCH2CH2CH2OH、-N (CH3)2、-N(CH3)CH2CH3、-NHOC(CH3)2NH2、-N(CH3)CH2Cyclopropyl ,-NHCH2Cyclopropyl ,-NH oxetanes Base ,-NCH2CH2Triazole, piperazinyl, piperidyl, pyrazolyl, azepine cycloheptatriene base, azetidinyl, methoxyl group and cyclopropyl Base amino,
The wherein phenyl, morpholino, triazolyl, imidazole radicals, azepine cycloheptatriene base, azetidinyl, pyrrolidines Base, piperazinyl, piperidyl, oxetanyl, cyclopropyl and pyrazolyl are optionally by 1-4 substituent groups independently selected from the following Replace: methyl, fluorine ,-NH2、-N(CH3)2, hydroxymethyl, oxo ,-OH and-CH2NH2,
Naphthenic base,
The naphthenic base replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH,
C1-6Alkyl, and
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Fluorine and chlorine；
Heterocyclylalkyl, and
The Heterocyclylalkyl replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine and chlorine,
C1-4Alkoxy, and
- OH, or
R53ccrAnd R54ccrNitrogen connected to them and optional 1-3 additional hetero atoms are formed together Heterocyclylalkyl, It is optionally replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Fluorine, chlorine, C1-4Alkoxy, oxo, phenyl, naphthenic base, Heterocyclylalkyl, methyl heterocycles alkyl ,-OH ,-NH2、-N(H) C1-5Alkyl, amino-heterocycles alkyl ,-N (C1-5Alkyl)2、-CN、-N(C1-4Alkyl) (CH2OCH3) and by 1 or 2 independently selected from - the NHC that substituent group below replaces1-4Alkyl: oxo, NH2With-OH,
Heterocyclylalkyl,
The Heterocyclylalkyl replaced by 1-9 substituent groups independently selected from the following: C1-6Alkyl ,-C1-6Alkyl OH, fluorine ,- C1-6Alkyl NH2, chlorine, oxo and-OH,
C1-4Alkoxy,
The C replaced by 1-4 substituent groups independently selected from the following1-4Alkoxy: fluorine, oxo ,-OH ,-COOH ,-NH2 With-CN,
- CN,
Oxo,
- OH,
-OP(O)(OH)2,
- COOH,
-CONH2,
-NH2,
-N(H)C1-4Alkyl,
- N (H) C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Fluorine, chlorine, C1-4Alkoxy, oxo, phenyl, naphthenic base, amino C1-4Alkoxy, Heterocyclylalkyl, methyl heterocycles alkane Base ,-OH ,-NH2,-N (H) C1-4Alkyl ,-N (C1-4Alkyl)2With-CN,
- O oxetanyl,
-ONHC(NH)NH2,
- NH cyclopropyl,
- NH oxetanyl,
-N(C1-4Alkyl)2,
-S(O)2CH2CH3,
S(O)2CH2CH2CH3,
-S(O)2CH3,
-S(O)2Phenyl,
Benzoyl,
Benzylamino,
Propylpyrrolidinyl,
Methylcyclopropyl groups,
Cyclobutylamino,
Cyclobutyl-N (CH3)-,
Piperidyl,
Imidazole radicals,
Morpholinyl,
Morpholinyl methyl,
Methyl piperazine ylmethyl,
Methyl piperazine base
Pyrrolidinyl,
Pyrrolidinylmethyl,
(methoxypyridylmethyl) amino,
Methylpyrrole alkyl,
Difluoropyrrolidin base,
Alkyl dimethyl pyrrole,
(methylcyclopropylmethyl) amino,
Hydroxymethyl-pyrrolidine base,
Fluoropyrrolidine base,
Fluorophenyl methyl amino,
Piperizinylmethyl,
Oxazolidinyl,
(methy oxetane ylmethyl) amino,
(methyl-cyclobutyl methyl) amino,
Oxoimidazolidinyl, and
2- hydroxyethylpiperidine base；
On condition that:
R53ccrAnd R54ccrIt is not all hydrogen；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, in formula (Vccr) compound, the compound is the form of phosphate prodrugs.
Suitably, in formula (Vccr) compound, the compound is-C (O) CH (NH2)CH(CH3)2The form of prodrug.
Suitably, in formula (Vccr) compound, R53ccrAnd R54ccrIt is not hydrogen.
Suitably, in formula (Vccr) compound, R52ccrFor the virtue replaced by 1-4 substituent groups independently selected from the following Base:
Fluorine,
Chlorine,
Tetrahydro-thiazoles base,
Tetrahydro-thiazoles base twice is replaced by oxo,
Tetrahydro thiazinyl,
Tetrahydro thiazinyl twice is replaced by oxo,
-N(CH3)S(O)2CH3,
-OS(O)2CH3,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Fluorine, chlorine, bromine, iodine, oxo ,-S (O)2CH3、-CN、-OR59With-NR56R57,
Wherein R56And R57Independently selected from: hydrogen ,-S (O)2CH3、C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR58R59Replace 1-6-OC1-5Alkane Base, wherein R58And R59Independently selected from: hydrogen, phenyl, C1-5Alkyl and replaced by 1-4 substituent groups independently selected from the following C1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl.
The present invention relates to the purposes of new formula (VIccr) compound and formula (VIccr) compound in the methods of the invention:
Wherein:
Y6ccrIt is selected from: S and NH；
R60ccrIt is selected from:
C1-3Alkyl,
The C replaced by 1-6 substituent groups independently selected from the following1-3Alkyl: fluorine and chlorine,
-N(H)C1-3Alkyl,
-N(C1-3Alkyl)2,
-SC1-4Alkyl,
C1-3Alkyl oxy,
Aryl,
The aryl replaced by 1-3 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH, and
C1-3Alkyl,
Heteroaryl,
The heteroaryl replaced by 1-3 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH, and
C1-3Alkyl,
Naphthenic base,
The naphthenic base replaced by 1-3 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH, and
C1-3Alkyl；
R62ccrIt is selected from:
Phenyl,
The phenyl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- CN,
Oxo,
C1-4Alkoxy,
The C replaced by 1-3 substituent groups independently selected from the following1-4Alkoxy:
Fluorine, chlorine, oxo ,-OH ,-NH2、-NHCH3With-N (CH3)2,
C1-6Alkyl,
The C replaced by 1-5 substituent groups independently selected from the following1-6Alkyl:
Fluorine, chlorine, bromine, iodine, oxo ,-S (O)2CH3、-CN、-OR69With-NR66R67,
Wherein R66And R67Independently selected from: hydrogen ,-S (O)2CH3、C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR68R69Replace 1-6-OC1-5Alkane Base, wherein R68And R69Independently selected from: hydrogen, phenyl, C1-5Alkyl and replaced by 1-4 substituent groups independently selected from the following C1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
Tetrahydro isothiazolyl,
Tetrahydro isothiazolyl twice is replaced by oxo,
Tetrahydro -1,2-thiazines base,
Tetrahydro twice -1,2-thiazines base is replaced by oxo,
-N(CH3)S(O)2CH3,
-N(CH3)S(O)2CFH2,
-N(CH3)S(O)2CF2H,
-N(CH3)S(O)2CF3,
-OS(O)2CH3,
-S(O)2NH2,
-S(O)2NHCH3, and
–NR80a’R81a’, wherein R80a’And R81a’Independently selected from: hydrogen ,-S (O)2CH3, phenyl, C1-5Alkyl and by 1-4 The C that substituent group independently selected from the following replaces1-5Alkyl: fluorine, oxo ,-OH ,-NH2、-OC1-5Alkyl is taken by fluorine and-COOH For 1-6-OC1-5Alkyl,
Heteroaryl, and
The heteroaryl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
C1-6Alkyl,
The C replaced by 1-5 substituent groups independently selected from the following1-6Alkyl:
Fluorine, chlorine, bromine, iodine, oxo ,-S (O)2CH3、-CN、-OR69With-NR66R67,
Wherein R66And R67Independently selected from: hydrogen ,-S (O)2CH3、C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR68R69Replace 1-6-OC1-5Alkane Base, wherein R68And R69Independently selected from: hydrogen, phenyl, C1-5Alkyl and replaced by 1-4 substituent groups independently selected from the following C1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
-S(O)2NH2, and
-S(O)2NHCH3；With
R63ccrAnd R64ccrIndependently selected from:
Hydrogen,
C1-4Alkyl,
The C replaced by 1-4 substituent groups independently selected from the following1-4Alkyl: phenyl, morpholino, triazolyl, imidazoles Base ,-CH2CH2Pyrrolidinyl ,-OC (O) NH2、-OCH2CH2NH2、-ONHC(NH2)NH2、-NHCH2C(CH3)3、-NOCH3、- NHOH、-NHCH2CH2F、-N(CH3)CH2CH2OCH3、-N(CH2CH3)2、-NCH(CH2OH)2、-N(CH2CH2OH)2、- NHCH2CH2OH、-NHCH2CH2NH2、-N(CH3)CH2(CH3)2CH2OH、-NHCH2CH3、-NHCH2CH2OCH3、-N(CH3) CH2CH2OH、-NHC(O)C(O)NH2、-N(CH3)CH2CH2CH2OH、-N(CH3)CH2CH(OH)CH2OH、-N(CH3)CH2CH2NH2、 Oxo ,-NHCH2C(CH3)2CH2OH、-OH、-NH2、-NHCH3、-NHCH2CH2CH2OH、-N(CH3)2、-N(CH3)CH2CH3、- NHOC(CH3)2NH2、-N(CH3)CH2Cyclopropyl ,-NHCH2Cyclopropyl ,-NH oxetanyl ,-NCH2CH2Triazole, piperazinyl, Piperidyl, pyrazolyl, azepine cycloheptatriene base, azetidinyl, methoxyl group and cyclopropylamino,
The wherein phenyl, morpholino, triazolyl, imidazole radicals, azepine cycloheptatriene base, azetidinyl, pyrrolidines Base, piperazinyl, piperidyl, oxetanyl, cyclopropyl and pyrazolyl are optionally by 1-4 substituent groups independently selected from the following Replace: methyl, fluorine ,-NH2、-N(CH3)2, hydroxymethyl, oxo ,-OH and-CH2NH2,
Naphthenic base,
The naphthenic base replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH, and
C1-6Alkyl,
Heterocyclylalkyl, and
The Heterocyclylalkyl replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH, and
C1-6Alkyl, or
R63ccrAnd R64ccrNitrogen connected to them and the optional 1-3 independently selected from O, N and S additional miscellaneous original Son is formed together Heterocyclylalkyl, is optionally replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH,
-OP(O)(OH)2,
- CN,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Fluorine, chlorine, C1-4Alkoxy, oxo, phenyl, naphthenic base, Heterocyclylalkyl, methyl heterocycles alkyl ,-OH ,-NH2、-N(H) C1-5Alkyl, amino-heterocycles alkyl ,-N (C1-5Alkyl)2、-CN、-N(C1-4Alkyl) (CH2OCH3) and be independently selected from below - the NHC that 1 or 2 substituent group replaces1-4Alkyl: oxo, NH2With-OH,
Heterocyclylalkyl,
The Heterocyclylalkyl replaced by 1-9 substituent groups independently selected from the following: C1-6Alkyl ,-C1-6Alkyl OH, fluorine, chlorine, Oxo and-OH,
C1-4Alkoxy,
The C replaced by 1-4 substituent groups independently selected from the following1-4Alkoxy: fluorine, oxo ,-OH ,-COOH ,-NH2 With-CN, oxo,
-NH2,
-N(H)C1-4Alkyl,
- N (H) C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Fluorine, chlorine, C1-4Alkoxy, oxo, phenyl, naphthenic base, amino C1-4Alkoxy, Heterocyclylalkyl, methyl heterocycles alkane Base ,-OH ,-NH2、-N(H)C1-4Alkyl ,-N (C1-4Alkyl)2With-CN,
-ONHC(NH)NH2,
- O oxetanyl,
-ONHC(NH)NH2,
- NH cyclopropyl,
- NH oxetanyl,
-N(C1-4Alkyl)2,
-S(O)2CH2CH3,
S(O)2CH2CH2CH3,
-S(O)2CH3,
-S(O)2Phenyl,
Benzoyl,
Benzylamino,
Propylpyrrolidinyl,
Methylcyclopropyl groups,
Cyclobutylamino,
Cyclobutyl-N (CH3)-,
Piperidyl,
Imidazole radicals,
Morpholinyl,
Morpholinyl methyl,
Methyl piperazine ylmethyl,
Methyl piperazine base,
Pyrrolidinyl,
Pyrrolidinylmethyl,
(methoxypyridylmethyl) amino,
Methylpyrrole alkyl,
Difluoropyrrolidin base,
Alkyl dimethyl pyrrole,
(methylcyclopropylmethyl) amino,
Hydroxymethyl-pyrrolidine base,
Fluoropyrrolidine base,
(fluorophenyl methyl) amino,
Piperizinylmethyl,
Oxazolidinyl,
(methy oxetane ylmethyl) amino,
(methyl-cyclobutyl methyl) amino,
Oxoimidazolidinyl, and
2- hydroxyethylpiperidine base；
On condition that:
R63ccrAnd R64ccrIt is not all hydrogen；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, in formula (VIccr) compound, the compound is the form of phosphate prodrugs.
Suitably, in formula (VIccr) compound, the compound is-C (O) CH (NH2)CH(CH3)2The form of prodrug.
Suitably, in formula (VIccr) compound, R63ccrAnd R64ccrIt is not hydrogen.
Suitably, in formula (VIccr) compound, R62ccrFor what is replaced by 1-4 substituent groups independently selected from the following Phenyl:
Fluorine,
Chlorine,
Tetrahydro isothiazolyl,
Tetrahydro isothiazolyl twice is replaced by oxo,
Tetrahydro -1,2-thiazines base,
Tetrahydro twice -1,2-thiazines base is replaced by oxo,
-N(CH3)S(O)2CH3,
-OS(O)2CH3,
C1-6Alkyl,
The C replaced by 1-5 substituent groups independently selected from the following1-6Alkyl:
Fluorine, chlorine, bromine, iodine, oxo ,-S (O)2CH3、-CN、-OR69With-NR66R67,
Wherein R66And R67Independently selected from: hydrogen ,-S (O)2CH3、C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR68R69Replace 1-6-OC1-5Alkane Base, wherein R68And R69Independently selected from: hydrogen, phenyl, C1-5Alkyl and replaced by 1-4 substituent groups independently selected from the following C1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl.
The present invention relates to the purposes of new formula (VIIccr) compound and formula (VIIccr) compound in the methods of the invention:
Wherein:
R70ccrIt is selected from:
Ethyl,
Replaced 1-4 ethyl by fluorine,
-NCH3,
-SCH3,
Ethyoxyl,
Methoxyl group,
Phenyl,
Furyl,
Cyclopropyl,
Replaced 1 or 2 cyclopropyl by fluorine；
R77ccrIt is selected from:
Phenyl,
The phenyl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- CN,
Oxo,
C1-4Alkoxy,
The C replaced by 1-3 substituent groups independently selected from the following1-4Alkoxy:
Fluorine, chlorine, oxo ,-OH ,-NH2,-NHCH3With-N (CH3)2,
C1-6Alkyl,
The C replaced by 1-3 substituent groups independently selected from the following1-6Alkyl:
Fluorine, chlorine, bromine, iodine, oxo ,-S (O)2CH3、-CN、-OR79aWith-NR76aR77a,
Wherein R76aAnd R77aIndependently selected from: hydrogen ,-S (O)2CH3、C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR78aR79aReplace 1-6-OC1-5 Alkyl, wherein R78aAnd R79aIndependently selected from: hydrogen, phenyl, C1-5It alkyl and is taken by 1-4 substituent groups independently selected from the following The C in generation1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
Tetrahydro isothiazolyl,
Tetrahydro isothiazolyl twice is replaced by oxo,
Tetrahydro -1,2-thiazines base,
Tetrahydro twice -1,2-thiazines base is replaced by oxo,
-N(CH3)S(O)2CH3,
-N(CH3)S(O)2CFH2,
-N(CH3)S(O)2CF2H,
-N(CH3)S(O)2CF3,
-OS(O)2CH3,
-S(O)2NH2,
-S(O)2NHCH3, and
–NR80a’R81a’, wherein R80a’And R81a’Independently selected from:
Hydrogen ,-S (O)2CH3, phenyl, C1-5Alkyl and the C replaced by 1-4 substituent groups independently selected from the following1-5Alkyl: Fluorine, oxo ,-OH ,-NH2、-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
Dihydropyridine base,
Oxo-dihydro pyridyl group,
Tetrahydro isoquinolyl,
By-C (O) CH3Substituted tetrahydro isoquinolyl,
Thiazolyl, and
The thiazolyl replaced by substituent group selected from the following :-C (O) CH3With-NHC (O) CH3；R72ccrAnd R73ccrIndependently It is selected from:
Hydrogen,
C1-4Alkyl,
The C replaced by 1-4 substituent groups independently selected from the following1-4Alkyl:
Phenyl, morpholino, triazolyl, imidazole radicals ,-CH2CH2Pyrrolidinyl ,-OC (O) NH2、-OCH2CH2NH2、-ONHC (NH2)NH2、-NHCH2C(CH3)3、-NOCH3、-NHOH、-NHCH2CH2F、-N(CH3)CH2CH2OCH3、-N(CH2CH3)2、-NCH (CH2OH)2、-N(CH2CH2OH)2、-NHCH2CH2OH、-NHCH2CH2NH2、-N(CH3)CH2(CH3)2CH2OH、-NHCH2CH3、- NHCH2CH2OCH3、-N(CH3)CH2CH2OH、-NHC(O)C(O)NH2、-N(CH3)CH2CH2CH2OH、-N(CH3)CH2CH(OH) CH2OH、-N(CH3)CH2CH2NH2, oxo ,-NHCH2C(CH3)2CH2OH、-OH、-NH2、-NHCH3、-NHCH2CH2CH2OH、-N (CH3)2、-N(CH3)CH2CH3、-NHOC(CH3)2NH2、-N(CH3)CH2Cyclopropyl ,-NHCH2Cyclopropyl ,-NH oxetanes Base ,-NCH2CH2Triazole, piperazinyl, piperidyl, pyrazolyl, azepine cycloheptatriene base, azetidinyl, methoxyl group and cyclopropyl Base amino,
The wherein phenyl, morpholino, triazolyl, imidazole radicals, azepine cycloheptatriene base, azetidinyl, pyrrolidines Base, piperazinyl, piperidyl, oxetanyl, cyclopropyl and pyrazolyl are optionally by 1-4 substituent groups independently selected from the following Replace: methyl, fluorine ,-NH2、-N(CH3)2, hydroxymethyl, oxo ,-OH and-CH2NH2,
Cyclobutyl,
Aminocyclobutyl,
Tetrahydrofuran,
5- oxa- -2- azaspiro [3.4] octyl, and
8- azabicyclo [3.2.1] octyl, or
R72ccrAnd R73ccrNitrogen connected to them and the optional 1-3 additional miscellaneous originals independently selected from O, N and S Son is formed together Heterocyclylalkyl, is selected from:
Pyrrolidinyl,
Pyrrolo- [3,4-c] pyrazolyl,
Piperidyl,
Isosorbide-5-Nitrae-Diazesuberane base,
Piperazinyl,
6,7- dihydros-triazol [4,5-c] pyridyl group,
2,9- diaza spiros [5.5] undecyl,
2,8- diaza spiros [4.5] decyl,
Octahydro -1H- pyrrolo- [1,2a] [Isosorbide-5-Nitrae] diaza cycloheptatriene base,
Oxa--diaza spiro [4.5] decyl,
Oxazolyl,
Morpholinyl,
1- oxa- -6- azaspiro [3.4] octyl,
2- oxa- -6- azaspiro [3.4] octyl,
1,7- diaza spiro [3.5] nonyl,
2,7- diaza spiros [3.5] nonyl,
2,6- diaza spiros [3.4] octyl,
Azetidinyl,
Hexahydropyrrolo simultaneously [3,4-b] oxazines base,
Dihydro phthalazinyl,
Diazabicyclo heptane base,
1,8- diaza spiro [4.5] decyl, and
5- oxa- -2- azaspiro [3.4] octyl,
All of which is optionally replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Oxo,
- OH,
-OP(O)(OH)2,
- CN,
-CH3,
-CH2OH,
Methoxyl group,
-CH2CH3,
-C(O)CH3,
-C(O)NH2,
-OCH2CH2OH,
-OCH2CH2NH2,
-ONHC(NH)NH2,
-OC(O)NH2,
- O oxetanyl,
-CH2CH2OH,
-CH2CH2CH2OH,
-CH2CH2CH3,
-CH2CH2OCH3,
-CH2CH(OH)CH3,
-CH2CH(OH)CH2OH,
-CH2C(O)OCH3,
-CH2C(O)NH2,
-C(O)CH(CH3)2,
-CH2CH2N(CH3)2,
-CH2CH2NHCH2CH3,
-CH2CH2CH2N(CH3)2,
-CH2CH2NHCH2C(CH3)3,
-CH2CH2N(CH3)CH2OCH3,
-C(CH3)2CH2OH,
-CH2C(CH3)2OH,
-CH2C(CH3)2OCH3,
-C(O)CH2OH,
-CH2Isothiazolyl,
-CH2Thiazolyl,
-CH2Pyrazolyl,
-CH2Imidazole radicals,
-CH2Pyridyl group,
-CH2Oxazolyl,
-CH2Pyrrole radicals,
-CH2Pyrrolidinyl,
-CH2Isoxazolyl,
-CH2Furyl,
-CH2CH2Morpholinyl,
-CH2CH2Pyrrolidinyl,
-CH2CH2Pyrrolidinyl CH3,
-CH2CH2CH2Pyrrolidinyl,
- C (O) phenyl,
- C (O) C (THP trtrahydropyranyl) NH2,
-NH2,
-NHCH3,
-N(CH3)2,
-NHC(O)CH3,
-NHCH(CH3)2,
-NHCH2CHF2,
-NHCH2C(CH3)3,
-NHCH2CH(CH3)2,
-NHCH2CH2OCH3,
-NHCH2CH2OH,
-NHCH2CH2NH2,
-NHCH2C (O) OH,
-NHC(O)CH2NH2,
-NHC(O)CH2CH2CH2NH2,
-NHCH2C(O)NH2,
-NHCH2C(OH)(CH3)2,
-NHC(O)CH(CH3)NH2,
-NHC(O)OCH(CH3)NH2,
-NHC(O)CH(CH3)2,
-NHC(O)C(CH3)3,
-NHC(O)C(CH3)2NH2,
-NHC(O)CH2OH,
-NHC(O)CH(CH2OH)NH2,
- NHC (O) (oxetanyl) NH2,
-NHC(O)OC(CH3)3,
-NHC(CH3)2C(O)OCH3,
- NH cyclopropyl,
- NH oxetanyl,
-CH2NH2,
-CH2CH2NH2,
-CH2CH2CH2NH2,
-CH2NHCH2C(CH3)3,
-CH2NHC(O)C(CH3)3,
-CH2NHC(O)CH2NH2,
-CH2NHC(O)CH2OH,
-CH2N(CH3)2,
-CH2NHCH3,
-CH2N(CH2CH3)2,
-CH2CH2N(CH3)2,
-S(O)2CH2CH3,
-S(O)2CH2CH2CH3,
-S(O)2Phenyl,
-S(O)2CH3,
Benzoyl,
Benzylamino,
Propylpyrrolidinyl,
Methylcyclopropyl groups,
Cyclobutylamino,
Cyclobutyl-N (CH3)-,
Piperidyl,
Imidazole radicals,
Morpholinyl,
Morpholinyl methyl,
Methyl piperazine ylmethyl,
Methyl piperazine base,
Pyrrolidinyl,
Pyrrolidinylmethyl,
(methoxypyridylmethyl) amino,
Methylpyrrole alkyl,
Difluoropyrrolidin base,
Alkyl dimethyl pyrrole,
(methylcyclopropylmethyl) amino,
Hydroxymethyl-pyrrolidine base,
Fluoropyrrolidine base,
(fluorophenyl methyl) amino,
Piperizinylmethyl,
Oxazolidinyl,
(methy oxetane ylmethyl) amino,
(methyl-cyclobutyl methyl) amino,
Oxoimidazolidinyl, and
2- hydroxyethylpiperidine base；
On condition that:
R72ccrAnd R73ccrIt is not all hydrogen；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, in formula (VIIccr) compound, the compound is the form of phosphate prodrugs.
Suitably, in formula (VIIccr) compound, the compound is-C (O) CH (NH2)CH(CH3)2The shape of prodrug Formula.
Suitably, in formula (VIIccr) compound, R72ccrAnd R73ccrIt is not hydrogen.
Suitably, in formula (VIIccr) compound, R77ccrFor what is replaced by 1-4 substituent groups independently selected from the following Phenyl:
Fluorine,
Chlorine,
- CN,
Oxo,
C1-4Alkoxy,
The C replaced by 1-3 substituent groups independently selected from the following1-4Alkoxy: fluorine, chlorine, oxo ,-OH ,-NH2、- NHCH3With
–N(CH3)2,
Tetrahydro isothiazolyl,
Tetrahydro isothiazolyl twice is replaced by oxo,
Tetrahydro -1,2-thiazines base,
Tetrahydro twice -1,2-thiazines base is replaced by oxo,
-N(CH3)S(O)2CH3,
-OS(O)2CH3,
C1-6Alkyl,
The C replaced by 1-3 substituent groups independently selected from the following1-6Alkyl:
Fluorine, chlorine, bromine, iodine, oxo ,-S (O)2CH3、-CN、-OR79aWith-NR76aR77a,
Wherein R76aAnd R77aIndependently selected from: hydrogen ,-S (O)2CH3、C1-5It alkyl and is taken by 1-4 is independently selected from the following The C replaced for base1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR78aR79aReplace 1-6-OC1-5 Alkyl, wherein R78aAnd R79aIndependently selected from: hydrogen, phenyl, C1-5It alkyl and is taken by 1-4 substituent groups independently selected from the following The C in generation1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl.
The present invention relates to the purposes of new formula (Qc) compound and formula (Qc) compound in the methods of the invention:
Wherein:
R70ca”It is selected from:
Ethyl,
-OCH3,
-CH2CF3, and
Cyclopropyl；
R77ca”It is selected from:
Phenyl,
The phenyl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- CN,
Oxo,
C1-4Alkoxy,
The C replaced by 1-3 substituent groups independently selected from the following1-4Alkoxy: fluorine, chlorine, oxo ,-OH ,-NH2、- NHCH3With
–N(CH3)2,
C1-6Alkyl,
The C replaced by 1-3 substituent groups independently selected from the following1-6Alkyl:
Fluorine, chlorine, bromine, iodine, oxo ,-S (O)2CH3、-CN、-OR79a’With-NR76a’R77a’,
Wherein R76a’And R77a’Independently selected from: hydrogen ,-S (O)2CH3、C1-5Alkyl and independently selected from the following by 1-4 The C that substituent group replaces1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR78a’R79a’Substitution 1-6 times- OC1-5Alkyl, wherein R78a’And R79a’Independently selected from: hydrogen, phenyl, C1-5Alkyl and by 1-4 substitutions independently selected from the following The C that base replaces1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
Tetrahydro isothiazolyl,
Tetrahydro isothiazolyl twice is replaced by oxo,
Tetrahydro -1,2-thiazines base,
Tetrahydro twice -1,2-thiazines base is replaced by oxo,
-N(CH3)S(O)2CFH2,
-N(CH3)S(O)2CF2H,
-N(CH3)S(O)2CF3,
-OS(O)2CH3,
-S(O)2NH2,
-S(O)2NHCH3, and
–NR80a’R81a’, wherein R80a’And R81a’Independently selected from: hydrogen ,-S (O)2CH3, phenyl, C1-5Alkyl and by 1-4 The C that substituent group independently selected from the following replaces1-5Alkyl: fluorine, oxo ,-OH ,-NH2、-OC1-5Alkyl is taken by fluorine and-COOH For 1-6-OC1-5Alkyl, and
R72ca”And R73ca”Independently selected from:
Hydrogen,
C1-4Alkyl,
The C replaced by 1-4 substituent groups independently selected from the following1-4Alkyl: phenyl, morpholino, triazolyl, imidazoles Base ,-CH2CH2Pyrrolidinyl ,-OC (O) NH2、-OCH2CH2NH2、-ONHC(NH2)NH2、-NHCH2C(CH3)3、-NOCH3、- NHOH、-NHCH2CH2F、-N(CH3)CH2CH2OCH3、-N(CH2CH3)2、-NCH(CH2OH)2、-N(CH2CH2OH)2、- NHCH2CH2OH、-NHCH2CH2NH2、-N(CH3)CH2(CH3)2CH2OH、-NHCH2CH3、-NHCH2CH2OCH3、-N(CH3) CH2CH2OH、-NHC(O)C(O)NH2、-N(CH3)CH2CH2CH2OH、-N(CH3)CH2CH(OH)CH2OH、-N(CH3)CH2CH2NH2、 Oxo ,-NHCH2C(CH3)2CH2OH、-OH、-NH2、-NHCH3、-NHCH2CH2CH2OH、-N(CH3)2、-N(CH3)CH2CH3、- NHOC(CH3)2NH2、-N(CH3)CH2Cyclopropyl ,-NHCH2Cyclopropyl ,-NH oxetanyl ,-NCH2CH2Triazole, piperazinyl, Piperidyl, pyrazolyl, azepine cycloheptatriene base, azetidinyl, methoxyl group and cyclopropylamino,
The wherein phenyl, morpholino, triazolyl, imidazole radicals, azepine cycloheptatriene base, azetidinyl, pyrrolidines Base, piperazinyl, piperidyl, oxetanyl, cyclopropyl and optionally replaced by 1-4 substituent groups independently selected from the following Pyrazolyl: methyl, fluorine ,-NH2、-N(CH3)2, hydroxymethyl, oxo ,-OH and-CH2NH2,
Cyclobutyl,
Aminocyclobutyl,
Tetrahydrofuran,
5- oxa- -2- azaspiro [3.4] octyl, and
8- azabicyclo [3.2.1] octyl, or
R72a”And R73a”Nitrogen connected to them and the optional 1-3 additional hetero atoms independently selected from O, N and S It is formed together Heterocyclylalkyl, is selected from:
Pyrrolidinyl,
Pyrrolo- [3,4-c] pyrazolyl,
Piperidyl,
Isosorbide-5-Nitrae-Diazesuberane base,
Piperazinyl,
6,7- dihydros-triazol [4,5-c] pyridyl group,
2,9- diaza spiros [5.5] undecyl,
2,8- diaza spiros [4.5] decyl,
Octahydro -1H- pyrrolo- [1,2a] [Isosorbide-5-Nitrae] diaza cycloheptatriene base,
Oxa--diaza spiro [4.5] decyl,
Oxazolyl,
Morpholinyl,
1- oxa- -6- azaspiro [3.4] octyl,
2- oxa- -6- azaspiro [3.4] octyl,
1,7- diaza spiro [3.5] nonyl,
2,7- diaza spiros [3.5] nonyl,
2,6- diaza spiros [3.4] octyl,
Azetidinyl,
Hexahydropyrrolo simultaneously [3,4-b] oxazines base,
Dihydro phthalazinyl,
Diazabicyclo heptane base,
1,8- diaza spiro [4.5] decyl, and
5- oxa- -2- azaspiro [3.4] octyl,
All of which is optionally replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Oxo,
- OH,
-OP(O)(OH)2,
- CN,
-CH3,
-CH2OH,
Methoxyl group,
-CH2CH3,
-C(O)CH3,
-C(O)NH2,
-OCH2CH2OH,
-OCH2CH2NH2,
-ONHC(NH)NH2,
-OC(O)NH2,
- O oxetanyl,
-CH2CH2OH,
-CH2CH2CH2OH,
-CH2CH2CH3,
-CH2CH2OCH3,
-CH2CH(OH)CH3,
-CH2CH(OH)CH2OH,
-CH2C(O)OCH3,
-CH2C(O)NH2,
-C(O)CH(CH3)2,
-CH2CH2N(CH3)2,
-CH2CH2NHCH2CH3,
-CH2CH2CH2N(CH3)2,
-CH2CH2NHCH2C(CH3)3,
-CH2CH2N(CH3)CH2OCH3,
-C(CH3)2CH2OH,
-CH2C(CH3)2OH,
-CH2C(CH3)2OCH3,
-C(O)CH2OH,
-CH2Isothiazolyl,
-CH2Thiazolyl,
-CH2Pyrazolyl,
-CH2Imidazole radicals,
-CH2Pyridyl group,
-CH2Oxazolyl,
-CH2Pyrrole radicals,
-CH2Pyrrolidinyl,
-CH2Isoxazolyl,
-CH2Furyl,
-CH2CH2Morpholinyl,
-CH2CH2Pyrrolidinyl,
-CH2CH2Pyrrolidinyl CH3,
-CH2CH2CH2Pyrrolidinyl,
- C (O) phenyl,
- C (O) C (THP trtrahydropyranyl) NH2,
-NH2,
-NHCH3,
-N(CH3)2,
-NHC(O)CH3,
-NHCH(CH3)2,
-NHCH2CHF2,
-NHCH2C(CH3)3,
-NHCH2CH(CH3)2,
-NHCH2CH2OCH3,
-NHCH2CH2OH,
-NHCH2CH2NH2,
-NHCH2C (O) OH,
-NHC(O)CH2NH2,
-NHC(O)CH2CH2CH2NH2,
-NHCH2C(O)NH2,
-NHCH2C(OH)(CH3)2,
-NHC(O)CH(CH3)NH2,
-NHC(O)OCH(CH3)NH2,
-NHC(O)CH(CH3)2,
-NHC(O)C(CH3)3,
-NHC(O)C(CH3)2NH2,
-NHC(O)CH2OH,
-NHC(O)CH(CH2OH)NH2,
- NHC (O) (oxetanyl) NH2,
-NHC(O)OC(CH3)3,
-NHC(CH3)2C(O)OCH3,
- NH cyclopropyl,
- NH oxetanyl,
-CH2NH2,
-CH2CH2NH2,
-CH2CH2CH2NH2,
-CH2NHCH2C(CH3)3,
-CH2NHC(O)C(CH3)3,
-CH2NHC(O)CH2NH2,
-CH2NHC(O)CH2OH,
-CH2N(CH3)2,
-CH2NHCH3,
-CH2N(CH2CH3)2,
-CH2CH2N(CH3)2,
-S(O)2CH2CH3,
-S(O)2CH2CH2CH3,
-S(O)2Phenyl,
-S(O)2CH3,
Benzoyl,
Benzylamino,
Propylpyrrolidinyl,
Methylcyclopropyl groups,
Cyclobutylamino,
Cyclobutyl-N (CH3)-,
Piperidyl,
Imidazole radicals,
Morpholinyl,
Morpholinyl methyl,
Methyl piperazine ylmethyl,
Methyl piperazine base,
Pyrrolidinyl,
Pyrrolidinylmethyl,
(methoxypyridylmethyl) amino,
Methylpyrrole alkyl,
Difluoropyrrolidin base,
Alkyl dimethyl pyrrole,
(methylcyclopropylmethyl) amino,
Hydroxymethyl-pyrrolidine base,
Fluoropyrrolidine base,
(fluorophenyl methyl) amino,
Piperizinylmethyl,
Oxazolidinyl,
(methy oxetane ylmethyl) amino,
(methyl-cyclobutyl methyl) amino,
Oxoimidazolidinyl, and
2- hydroxyethylpiperidine base；
On condition that:
R72a”And R73a”It is not all hydrogen；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, in formula (Qc) compound, the compound is the form of phosphate prodrugs.
Suitably, in formula (Qc) compound, the compound is-C (O) CH (NH2)CH(CH3)2The form of prodrug.
Suitably, in formula (Qc) compound, R72a”And R73a”It is not hydrogen.
The present invention relates to the purposes of new formula (Qc1) compound and formula (Qc1) compound in the methods of the invention:
Wherein:
R70ca1”It is selected from:
Ethyl,
-OCH3,
-CH2CF3, and
Cyclopropyl；
R77ca1”It is selected from:
Phenyl,
The phenyl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- CN,
Oxo,
C1-4Alkoxy,
The C replaced by 1-3 substituent groups independently selected from the following1-4Alkoxy: fluorine, chlorine, oxo ,-OH ,-NH2、- NHCH3With
–N(CH3)2,
C1-6Alkyl,
The C replaced by 1-3 substituent groups independently selected from the following1-6Alkyl:
Fluorine, chlorine, bromine, iodine, oxo ,-S (O)2CH3、-CN、-OR79a’With-NR76a’R77a’,
Wherein R76a’And R77a’Independently selected from: hydrogen ,-S (O)2CH3、C1-5Alkyl and independently selected from the following by 1-4 The C that substituent group replaces1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR78a’R79a’Substitution 1-6 times- OC1-5Alkyl, wherein R78a’And R79a’Independently selected from: hydrogen, phenyl, C1-5Alkyl and by 1-4 substitutions independently selected from the following The C that base replaces1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
Tetrahydro isothiazolyl,
Tetrahydro isothiazolyl twice is replaced by oxo,
Tetrahydro -1,2-thiazines base,
Tetrahydro twice -1,2-thiazines base is replaced by oxo,
-OS(O)2CH3,
-N(CH3)S(O)2CH3,
-N(CH3)S(O)2CFH2,
-N(CH3)S(O)2CF2H,
-N(CH3)S(O)2CF3,
-S(O)2NH2,
-S(O)2NHCH3, and
–NR80a’R81a’, wherein R80a’And R81a’Independently selected from: hydrogen ,-S (O)2CH3, phenyl, C1-5Alkyl and by 1-4 The C that substituent group independently selected from the following replaces1-5Alkyl: fluorine, oxo ,-OH ,-NH2、-OC1-5Alkyl is taken by fluorine and-COOH For 1-6-OC1-5Alkyl, and
R72ca1”And R73ca1”Independently selected from:
C1-4Alkyl,
The C replaced by 1-4 substituent groups independently selected from the following1-4Alkyl: phenyl, morpholino, triazolyl, imidazoles Base ,-CH2CH2Pyrrolidinyl ,-OC (O) NH2、-OCH2CH2NH2、-ONHC(NH2)NH2、-NHCH2C(CH3)3、-NOCH3、- NHOH、-NHCH2CH2F、-N(CH3)CH2CH2OCH3、-N(CH2CH3)2、-NCH(CH2OH)2、-N(CH2CH2OH)2、- NHCH2CH2OH、-NHCH2CH2NH2、-N(CH3)CH2(CH3)2CH2OH、-NHCH2CH3、-NHCH2CH2OCH3、-N(CH3) CH2CH2OH、-NHC(O)C(O)NH2、-N(CH3)CH2CH2CH2OH、-N(CH3)CH2CH(OH)CH2OH、-N(CH3)CH2CH2NH2、 Oxo ,-NHCH2C(CH3)2CH2OH、-OH、-NH2、-NHCH3、-NHCH2CH2CH2OH、-N(CH3)2、-N(CH3)CH2CH3、- NHOC(CH3)2NH2、-N(CH3)CH2Cyclopropyl ,-NHCH2Cyclopropyl ,-NH oxetanyl ,-NCH2CH2Triazole, piperazinyl, Piperidyl, pyrazolyl, azepine cycloheptatriene base, azetidinyl, methoxyl group and cyclopropylamino,
The wherein phenyl, morpholino, triazolyl, imidazole radicals, azepine cycloheptatriene base, azetidinyl, pyrrolidines Base, piperazinyl, piperidyl, oxetanyl, cyclopropyl and optionally replaced by 1-4 substituent groups independently selected from the following Pyrazolyl: methyl, fluorine ,-NH2、-N(CH3)2, hydroxymethyl, oxo ,-OH and-CH2NH2,
Cyclobutyl,
Aminocyclobutyl,
Tetrahydrofuran,
5- oxa- -2- azaspiro [3.4] octyl, and
8- azabicyclo [3.2.1] octyl, or
R72ca1”And R73ca1”Nitrogen connected to them and optional 1-3 additional hetero atoms are formed together heterocycle alkane Base is selected from:
Pyrrolidinyl,
Pyrrolo- [3,4-c] pyrazolyl,
Piperidyl,
Isosorbide-5-Nitrae-Diazesuberane base,
Piperazinyl,
6,7- dihydros-triazol [4,5-c] pyridyl group,
2,9- diaza spiros [5.5] undecyl,
2,8- diaza spiros [4.5] decyl,
Octahydro -1H- pyrrolo- [1,2a] [Isosorbide-5-Nitrae] diaza cycloheptatriene base,
Oxa--diaza spiro [4.5] decyl,
Oxazolyl,
Morpholinyl,
1- oxa- -6- azaspiro [3.4] octyl,
2- oxa- -6- azaspiro [3.4] octyl,
1,7- diaza spiro [3.5] nonyl,
2,7- diaza spiros [3.5] nonyl,
2,6- diaza spiros [3.4] octyl,
Azetidinyl,
Hexahydropyrrolo simultaneously [3,4-b] oxazines base,
Dihydro phthalazinyl,
Diazabicyclo heptane base,
1,8- diaza spiro [4.5] decyl, and
5- oxa- -2- azaspiro [3.4] octyl,
All of which is optionally replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Oxo,
- OH,
- CN,
-CH3,
-CH2OH,
Methoxyl group,
-CH2CH3,
-C(O)CH3,
-C(O)NH2,
-OCH2CH2OH,
-OCH2CH2NH2,
-ONHC(NH)NH2,
-OC(O)NH2,
- O oxetanyl,
-CH2CH2OH,
-CH2CH2CH2OH,
-CH2CH2CH3,
-CH2CH2OCH3,
-CH2CH(OH)CH3,
-CH2CH(OH)CH2OH,
-CH2C(O)OCH3,
-CH2C(O)NH2,
-C(O)CH(CH3)2,
-CH2CH2N(CH3)2,
-CH2CH2NHCH2CH3,
-CH2CH2CH2N(CH3)2,
-CH2CH2NHCH2C(CH3)3,
-CH2CH2N(CH3)CH2OCH3,
-C(CH3)2CH2OH,
-CH2C(CH3)2OH,
-CH2C(CH3)2OCH3,
-C(O)CH2OH,
-CH2Isothiazolyl,
-CH2Thiazolyl,
-CH2Pyrazolyl,
-CH2Imidazole radicals,
-CH2Pyridyl group,
-CH2Oxazolyl,
-CH2Pyrrole radicals,
-CH2Pyrrolidinyl,
-CH2Isoxazolyl,
-CH2Furyl,
-CH2CH2Morpholinyl,
-CH2CH2Pyrrolidinyl,
-CH2CH2Pyrrolidinyl CH3,
-CH2CH2CH2Pyrrolidinyl,
- C (O) phenyl,
- C (O) C (THP trtrahydropyranyl) NH2,
-NH2,
-NHCH3,
-N(CH3)2,
-NHC(O)CH3,
-NHCH(CH3)2,
-NHCH2CHF2,
-NHCH2C(CH3)3,
-NHCH2CH(CH3)2,
-NHCH2CH2OCH3,
-NHCH2CH2OH,
-NHCH2CH2NH2,
-NHCH2C (O) OH,
-NHC(O)CH2NH2,
-NHC(O)CH2CH2CH2NH2,
-NHCH2C(O)NH2,
-NHCH2C(OH)(CH3)2,
-NHC(O)CH(CH3)NH2,
-NHC(O)OCH(CH3)NH2,
-NHC(O)CH(CH3)2,
-NHC(O)C(CH3)3,
-NHC(O)C(CH3)2NH2,
-NHC(O)CH2OH,
-NHC(O)CH(CH2OH)NH2,
- NHC (O) (oxetanyl) NH2,
-NHC(O)OC(CH3)3,
-NHC(CH3)2C(O)OCH3,
- NH cyclopropyl,
- NH oxetanyl,
-CH2NH2,
-CH2CH2NH2,
-CH2CH2CH2NH2,
-CH2NHCH2C(CH3)3,
-CH2NHC(O)C(CH3)3,
-CH2NHC(O)CH2NH2,
-CH2NHC(O)CH2OH,
-CH2N(CH3)2,
-CH2NHCH3,
-CH2N(CH2CH3)2,
-CH2CH2N(CH3)2,
-S(O)2CH2CH3,
-S(O)2CH2CH2CH3,
-S(O)2Phenyl,
-S(O)2CH3,
Benzoyl,
Benzylamino,
3- pyrrolidinylpropyl,
2- Cvclopropvlmethvl,
Cyclobutylamino,
Cyclobutyl-N (CH3)-,
Piperidyl,
Imidazole radicals,
Morpholinyl,
Morpholinyl methyl,
Methyl piperazine ylmethyl,
Methyl piperazine base,
Pyrrolidinyl,
Pyrrolidinylmethyl,
Methoxypyridylmethyl amino,
Methylpyrrole alkyl,
Difluoropyrrolidin base,
Alkyl dimethyl pyrrole,
Methylcyclopropylmethyl amino,
Hydroxymethyl-pyrrolidine base,
Fluoropyrrolidine base,
Fluorophenyl methyl amino,
Piperizinylmethyl,
Oxazolidinyl,
Methy oxetane vlmethyl,
Methyl-cyclobutyl methylamino,
Oxoimidazolidinyl, and
2- hydroxyethylpiperidine base；
On condition that:
R72ca1”And R73ca1”It is not all unsubstituted alkyl；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, in formula (Qc1) compound, the compound is the form of phosphate prodrugs.
Suitably, in formula (Qc1) compound, the compound is-C (O) CH (NH2)CH(CH3)2The form of prodrug.
The present invention relates to the purposes of new formula (Qc2) compound and formula (Qc2) compound in the methods of the invention:
Wherein:
R70ca2”It is selected from:
Ethyl,
-OCH3,
-CH2CF3, and
Cyclopropyl；
R77ca2”It is selected from:
Phenyl,
The phenyl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- CN,
Oxo,
C1-4Alkoxy,
The C replaced by 1-3 substituent groups independently selected from the following1-4Alkoxy: fluorine, chlorine, oxo ,-OH ,-NH2、- NHCH3With
–N(CH3)2,
C1-6Alkyl,
The C replaced by 1-3 substituent groups independently selected from the following1-6Alkyl:
Fluorine, chlorine, bromine, iodine, oxo ,-S (O)2CH3、-CN、-OR79a’With-NR76a’R77a’,
Wherein R76a’And R77a’Independently selected from: hydrogen ,-S (O)2CH3、C1-5Alkyl and independently selected from the following by 1-4 The C that substituent group replaces1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5Alkyl, by fluorine ,-COOH and-NR78a’R79a’Substitution 1-6 times- OC1-5Alkyl, wherein R78a’And R79a’Independently selected from: hydrogen, phenyl, C1-5Alkyl and by 1-4 substitutions independently selected from the following The C that base replaces1-5Alkyl: fluorine, oxo ,-OH ,-OC1-5The alkyl ,-OC for being replaced 1-6 times by fluorine and-COOH1-5Alkyl,
Tetrahydro isothiazolyl,
Tetrahydro isothiazolyl twice is replaced by oxo,
Tetrahydro -1,2-thiazines base,
Tetrahydro twice -1,2-thiazines base is replaced by oxo,
-N(CH3)S(O)2CH3,
-N(CH3)S(O)2CFH2,
-N(CH3)S(O)2CF2H,
-N(CH3)S(O)2CF3,
-OS(O)2CH3,
-S(O)2NH2,
-S(O)2NHCH3, and
–NR80a’R81a’, wherein R80a’And R81a’Independently selected from: hydrogen ,-S (O)2CH3, phenyl, C1-5Alkyl and by 1-4 The C that substituent group independently selected from the following replaces1-5Alkyl: fluorine, oxo ,-OH ,-NH2、-OC1-5Alkyl is taken by fluorine and-COOH For 1-6-OC1-5Alkyl, and
R72ca2”And R73ca2”Nitrogen connected to them and optional 1-3 additional hetero atoms are formed together heterocycle alkane Base is selected from:
Pyrrolidinyl,
Pyrrolo- [3,4-c] pyrazolyl,
Piperidyl,
Isosorbide-5-Nitrae-Diazesuberane base,
Piperazinyl,
6,7- dihydros-triazol [4,5-c] pyridyl group,
2,9- diaza spiros [5.5] undecyl,
2,8- diaza spiros [4.5] decyl,
Octahydro -1H- pyrrolo- [1,2a] [Isosorbide-5-Nitrae] diaza cycloheptatriene base,
Oxa--diaza spiro [4.5] decyl,
Oxazolyl,
Morpholinyl,
1- oxa- -6- azaspiro [3.4] octyl,
2- oxa- -6- azaspiro [3.4] octyl,
1,7- diaza spiro [3.5] nonyl,
2,7- diaza spiros [3.5] nonyl,
2,6- diaza spiros [3.4] octyl,
Azetidinyl,
Hexahydropyrrolo simultaneously [3,4-b] oxazines base,
Dihydro phthalazinyl,
Diazabicyclo heptane base,
1,8- diaza spiro [4.5] decyl, and
5- oxa- -2- azaspiro [3.4] octyl,
All of which is optionally replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Oxo,
- OH,
- CN,
-CH3,
-CH2OH,
Methoxyl group,
-CH2CH3,
-C(O)CH3,
-C(O)NH2,
-OCH2CH2OH,
-OCH2CH2NH2,
-ONHC(NH)NH2,
-OC(O)NH2,
- O oxetanyl,
-CH2CH2OH,
-CH2CH2CH2OH,
-CH2CH2CH3,
-CH2CH2OCH3,
-CH2CH(OH)CH3,
-CH2CH(OH)CH2OH,
-CH2C(O)OCH3,
-CH2C(O)NH2,
-C(O)CH(CH3)2,
-CH2CH2N(CH3)2,
-CH2CH2NHCH2CH3,
-CH2CH2CH2N(CH3)2,
-CH2CH2NHCH2C(CH3)3,
-CH2CH2N(CH3)CH2OCH3,
-C(CH3)2CH2OH,
-CH2C(CH3)2OH,
-CH2C(CH3)2OCH3,
-C(O)CH2OH,
-CH2Isothiazolyl,
-CH2Thiazolyl,
-CH2Pyrazolyl,
-CH2Imidazole radicals,
-CH2Pyridyl group,
-CH2Oxazolyl,
-CH2Pyrrole radicals,
-CH2Pyrrolidinyl,
-CH2Isoxazolyl,
-CH2Furyl,
-CH2CH2Morpholinyl,
-CH2CH2Pyrrolidinyl,
-CH2CH2Pyrrolidinyl CH3,
-CH2CH2CH2Pyrrolidinyl,
- C (O) phenyl,
- C (O) C (THP trtrahydropyranyl) NH2,
-NH2,
-NHCH3,
-N(CH3)2,
-NHC(O)CH3,
-NHCH(CH3)2,
-NHCH2CHF2,
-NHCH2C(CH3)3,
-NHCH2CH(CH3)2,
-NHCH2CH2OCH3,
-NHCH2CH2OH,
-NHCH2CH2NH2,
-NHCH2C (O) OH,
-NHC(O)CH2NH2,
-NHC(O)CH2CH2CH2NH2,
-NHCH2C(O)NH2,
-NHCH2C(OH)(CH3)2,
-NHC(O)CH(CH3)NH2,
-NHC(O)OCH(CH3)NH2,
-NHC(O)CH(CH3)2,
-NHC(O)C(CH3)3,
-NHC(O)C(CH3)2NH2,
-NHC(O)CH2OH,
-NHC(O)CH(CH2OH)NH2,
- NHC (O) (oxetanyl) NH2,
-NHC(O)OC(CH3)3,
-NHC(CH3)2C(O)OCH3,
- NH cyclopropyl,
- NH oxetanyl,
-CH2NH2,
-CH2CH2NH2,
-CH2CH2CH2NH2,
-CH2NHCH2C(CH3)3,
-CH2NHC(O)C(CH3)3,
-CH2NHC(O)CH2NH2,
-CH2NHC(O)CH2OH,
-CH2N(CH3)2,
-CH2NHCH3,
-CH2N(CH2CH3)2,
-CH2CH2N(CH3)2,
-S(O)2CH2CH3,
-S(O)2CH2CH2CH3,
-S(O)2Phenyl,
-S(O)2CH3,
Benzoyl,
Benzylamino,
3- pyrrolidinylpropyl,
2- Cvclopropvlmethvl,
Cyclobutylamino,
Cyclobutyl-N (CH3)-,
Piperidyl,
Imidazole radicals,
Morpholinyl,
Morpholinyl methyl,
Methyl piperazine ylmethyl,
Methyl piperazine base,
Pyrrolidinyl,
Pyrrolidinylmethyl,
Methoxypyridylmethyl amino,
Methylpyrrole alkyl,
Difluoropyrrolidin base,
Alkyl dimethyl pyrrole,
Methylcyclopropylmethyl amino,
Hydroxymethyl-pyrrolidine base,
Fluoropyrrolidine base,
Fluorophenyl methyl amino,
Piperizinylmethyl,
Oxazolidinyl,
Methy oxetane vlmethyl,
Methyl-cyclobutyl methylamino,
Oxoimidazolidinyl, and
2- hydroxyethylpiperidine base；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, in formula (Qc2) compound, the compound is the form of phosphate prodrugs.
Suitably, in formula (Qc2) compound, the compound is-C (O) CH (NH2)CH(CH3)2The form of prodrug.
In one embodiment, X51aIt is selected from :-CN, fluorine and chlorine.In one embodiment, X52aBe selected from :-CN, fluorine and Chlorine.In one embodiment, X51aFor-CN.In one embodiment, X52aFor-CN.
In one embodiment, Y5aIt is selected from: S and NH.In one embodiment, Y5aFor S.
In one embodiment, Y5bbrFor S.
In one embodiment, R50aIt is selected from: C1-6Alkyl is replaced by the 1-9 substituent groups independently selected from fluorine and chlorine C1-6Alkyl and naphthenic base.In one embodiment, R50aSelected from ethyl, cyclopropyl and 2,2,2- trifluoroethyl.At one In embodiment, R50aFor ethyl.
In one embodiment, R50bbrIt is selected from: C1-6Alkyl is replaced by the 1-9 substituent groups independently selected from fluorine and chlorine C1-6Alkyl and naphthenic base.In one embodiment, R50bbrSelected from ethyl, cyclopropyl and 2,2,2- trifluoroethyl.One In a embodiment, R50bbrFor ethyl.
In one embodiment, R50aarIt is selected from: phenyl, furyl, C1-6Alkyl, by 1-9 independently selected from fluorine and chlorine Substituent group replace C1-6Alkyl and naphthenic base.In one embodiment, R50aarSelected from phenyl, furyl, ethyl, cyclopropyl Base and 2,2,2- trifluoroethyl.In one embodiment, R50aarFor ethyl.In one embodiment, R50aarFor phenyl. In one embodiment, R50aarFor furyl.
In one embodiment, R51aIt is selected from: hydrogen, C1-6Alkyl, aryl, chlorphenyl and heteroaryl.In an embodiment party In case, R51aIt is selected from: hydrogen, methyl, phenyl, chlorphenyl and pyridine.In one embodiment, R51aFor phenyl.Implement at one In scheme, R51aFor hydrogen.
In one embodiment, R51bbrIt is selected from: hydrogen, C1-6Alkyl, aryl, chlorphenyl and heteroaryl.In an embodiment party In case, R51bbrIt is selected from: hydrogen, methyl, phenyl, chlorphenyl, piperidyl and pyridyl group.In one embodiment, R51bbrFor benzene Base.In one embodiment, R51bbrFor pyridyl group.
In one embodiment, R52aIt is selected from :-C (O) NH2With-phenyl CH2NHC(O)CH3.In one embodiment, R52aFor-C (O) NH2.In one embodiment, R52aFor-phenyl CH2NHC(O)CH3。
In one embodiment, R53aAnd R54aIndependently selected from: hydrogen, methyl, morpholinoethyl, methoxy ethyl, oxygen Miscellaneous azaspiro [3.4] octyl, 5- oxa- -2- azaspiro [3.4] octyl, amino-ethyl, amino -2- oxoethyl and hydroxyl second Base.
In one embodiment, R53aAnd R54aNitrogen connected to them is formed together: pyrrolidinyl, hydroxyl pyrrolidine Base, piperidyl, hydroxy piperidine base, 1,4- Diazesuberane base, methyl-1,4- Diazesuberane base, methoxy ethyl -1, 4- Diazesuberane base, hydroxypropyl -1,4- Diazesuberane base, methyl-1,4- Diazesuberane yl acetate, (methyl) oxo -1,4- Diazesuberane base, (methyl) oxopiperazinyl, propylpiperazinyl, amino-pyrroles alkyl, oxo - 1,4- Diazesuberane base, piperidinyl piperazine base, hydroxymethylpiperazin base, oxopiperazinyl, morpholinyl piperidyl, hydroxyl second Base 1,4- Diazesuberane base, dimethylaminopropyl piperazinyl, pyrrolidinyl piperidyl, piperidinyl piperidine base, pyrrolidines Base propyl -1,4- Diazesuberane base, methyl piperazine base, dimethylaminopyridine base, lupetazin base, thebaine Base, (amino methyl) hydroxy piperidine base, amino piperidine base, methylamino piperidyl, piperazinyl, aminoethylpiperazine base, ethyl Piperazinyl, morpholinyl A phenylpiperidines base, aminopropylpiperazine base, methyl piperazine ylmethylpiperidine base, pyrrolidinylmethyl piperidines Base, methyl piperazine phenylpiperidines base, ethyl 1,4- Diazesuberane base, imidazolinyl piperidyl, oxoimidazolinium phenylpiperidines base, Propyl -1,4- Diazesuberane base, azetidinyl, methoxyl group azetidinyl, acetylpiperazinyl, hydroxyethyl Piperazinyl, morpholinyl, 2- methylpropionyl piperazinyl, ethanesulfonyl piperazinyl, methanesulfonylpiperazin base, benzoyl piperazine Piperazine base, oxo-piperidine base, hydroxyethylpiperidine phenylpiperidines base, hydroxymethyl morpholinyl or dif luoropiperidinyl.
In one embodiment, R53And R54Nitrogen connected to them is formed together: diaza spiro undecyl, 2, 9- diaza spiro [5.5] undecyl, diaza spiro decyl, 2,8- diaza spiro [4.5] decyl, hexahydropyrrolo simultaneously -1,4- two Nitrogen heterocyclic heptyl, methyl -2,9- diaza spiro [5.5] undecyl, Cvclopropvlmethvl -2,9- diaza spiro [5.5] 11 Alkyl, oxazepine spiral shell octyl, oxazepine spiral shell [3.4] octyl, diaza spiro nonyl, diaza spiro [3.5] nonane Base, 1,7- diaza spiro [3.5] nonyl, 2,7- diaza spiro [3.5] nonyl, diaza spiro octyl, diaza spiro [3.4] octyl, 2,6- diaza spiro [3.4] octyl, methane sulfonyl -1,8- diaza spiro [4.5] decyl, azabicyclo And octyl, 8- azabicyclo [3.2.1] octyl, 4- amino -4- methyl piperidine -1- base, NH2CH2C (O) NH- piperidyl, NH2CH(CH3) C (O) NH- piperidyl, 3- amino oxetanes -3- carbonyl) piperazinyl, 4- amino-(piperidin-4-yl) tetrahydro - 2H- pyrans -4- formamide, 4- amino-(piperazine -4- base) tetrahydro -2H- pyrans -4- formamide, hydroxyethyl -1,4- diaza Cycloheptyl alkyl, amino piperidine base, hydroxy azetidine base, hydroxypyrrole alkyl or hydroxyl-oxethyl piperidyl.
In one embodiment, R53bbrAnd R54bbrIndependently selected from: hydrogen, methyl, morpholinoethyl, methoxy ethyl, Oxazepine spiral shell [3.4] octyl, 5- oxa- -2- azaspiro [3.4] octyl, amino-ethyl, amino -2- oxoethyl and hydroxyl second Base.
In one embodiment, R53bbrAnd R54bbrNitrogen connected to them is formed together: pyrrolidinyl, hydroxyl pyrrole Cough up alkyl, piperidyl, hydroxy piperidine base, 1,4- Diazesuberane base, methyl-1,4- Diazesuberane base, methoxyl group second Base -1,4- Diazesuberane base, hydroxypropyl -1,4- Diazesuberane base, methyl-1,4- Diazesuberane guanidine-acetic acid Ester, (methyl) oxo -1,4- Diazesuberane base, (methyl) oxopiperazinyl, propylpiperazinyl, amino-pyrroles alkyl, oxygen Generation -1,4- Diazesuberane base, piperidinyl piperazine base, hydroxymethylpiperazin base, oxopiperazinyl, morpholinyl piperidyl, hydroxyl Base ethyl 1,4- Diazesuberane base, dimethylaminopropyl piperazinyl, pyrrolidinyl piperidyl, piperidinyl piperidine base, pyrrole Cough up alkyl propyl -1,4- Diazesuberane base, methyl piperazine base, dimethylaminopyridine base, lupetazin base, dimethyl Morpholinyl, (amino methyl) hydroxy piperidine base, amino piperidine base, methylamino piperidyl, piperazinyl, aminoethylpiperazine base, Ethyl piperazidine base, morpholinyl A phenylpiperidines base, aminopropylpiperazine base, methyl piperazine ylmethylpiperidine base, pyrrolidinylmethyl Piperidyl, methyl piperazine phenylpiperidines base, ethyl 1,4- Diazesuberane base, imidazolinyl piperidyl, oxoimidazolinium base piperazine Piperidinyl, propyl -1,4- Diazesuberane base, azetidinyl, methoxyl group azetidinyl, acetylpiperazinyl, hydroxyl Base ethyl piperazidine base, morpholinyl, 2- methylpropionyl piperazinyl, ethanesulfonyl piperazinyl, methanesulfonylpiperazin base, benzene first Acyl piperazine base, oxo-piperidine base, hydroxyethylpiperidine phenylpiperidines base, hydroxymethyl morpholinyl or dif luoropiperidinyl.
In one embodiment, R53bbrAnd R54bbrNitrogen connected to them is formed together: diaza spiro hendecane Base, 2,9- diaza spiro [5.5] undecyl, diaza spiro decyl, 2,8- diaza spiro [4.5] decyl, hexahydropyrrolo simultaneously -1, 4- Diazesuberane base, methyl -2,9- diaza spiro [5.5] undecyl, Cvclopropvlmethvl -2,9- diaza spiro [5.5] Undecyl, oxazepine spiral shell octyl, oxazepine spiral shell [3.4] octyl, diaza spiro nonyl, diaza spiro [3.5] Nonyl, 1,7- diaza spiro [3.5] nonyl, 2,7- diaza spiro [3.5] nonyl, diaza spiro octyl, diaza Spiral shell [3.4] octyl, 2,6- diaza spiro [3.4] octyl, methane sulfonyl -1,8- diaza spiro [4.5] decyl, azepine are double Ring and octyl, 8- azabicyclo [3.2.1] octyl, 4- amino -4- methyl piperidine -1- base, NH2CH2C (O) NH- piperidyl, NH2CH(CH3) C (O) NH- piperidyl, 3- amino oxetanes -3- carbonyl) piperazinyl, 4- amino-(piperidin-4-yl) tetrahydro - 2H- pyrans -4- formamide, 4- amino-(piperazine -4- base) tetrahydro -2H- pyrans -4- formamide, hydroxyethyl -1,4- diaza Cycloheptyl alkyl, amino piperidine base, hydroxy azetidine base, hydroxypyrrole alkyl or hydroxyl-oxethyl piperidyl.
In one embodiment, X41ccrIt is selected from :-CN, fluorine and chlorine.In one embodiment, X42ccrIt is selected from :-CN, Fluorine and chlorine.In one embodiment, X41ccrFor-CN.In one embodiment, X42ccrFor-CN.
In one embodiment, Y4ccrIt is selected from: S and NH.In one embodiment, Y4ccrFor S.
In one embodiment, R41ccrIt is selected from: C1-6Alkyl is replaced by the 1-9 substituent groups independently selected from fluorine and chlorine C1-6Alkyl and naphthenic base.In one embodiment, R41ccrSelected from ethyl, cyclopropyl and 2,2,2, trifluoroethyl.One In a embodiment, R41ccrFor ethyl.
In one embodiment, R43ccrBe selected from: phenyl is independently selected from the benzene that 1 or 2 substituent group below replaces Base :-OS (O)2CH3、-N(CH3)S(O)2CH3、-CH2NHC(O)CH3、-CH2NHC(O)CH2NH2、-CH2NHC(O)CH3, tetrahydro thiophene Oxazolyl, the tetrahydro-thiazoles base for being replaced 1 or 2 time by oxo, tetrahydro thiazinyl, the tetrahydro thiazinyl for being replaced by oxo 1 or 2 time and- CH2S(O)2CH3。
In one embodiment, R44ccrAnd R45ccrIndependently selected from: hydrogen, methyl and by 1-9 independently selected from following Substituent group replace C1-6Alkyl :-N (CH2CH3)2With
-NHOC(CH3)2NH2。
In one embodiment, R44ccrAnd R45ccrNitrogen connected to them is formed together: piperidyl, by 1 or 2 Independently selected from amino ,-NHCH (CH3), pyrrolidinyl ,-NHC (O) C (CH3)3、-NH(O)CH(CH3)(NH2), fluorine, chlorine and CH2N(CH3)2Substituent group replace piperidyl, morpholinyl, by CH2The morpholinyl of pyrrolidinyl substitution, 1,4- diaza cycloheptyl Alkyl and methyl 1,4- Diazesuberane base.
In one embodiment, X41bbrIt is selected from :-CN, fluorine and chlorine.In one embodiment, X42bbrIt is selected from :-CN, Fluorine and chlorine.In one embodiment, X41bbrFor-CN.In one embodiment, X42bbrFor-CN.
In one embodiment, Y4bbrIt is selected from: S and NH.In one embodiment, Y4bbrFor S.
In one embodiment, R41bbrIt is selected from: C1-6Alkyl is replaced by the 1-9 substituent groups independently selected from fluorine and chlorine C1-6Alkyl and naphthenic base.In one embodiment, R41bbrSelected from ethyl, cyclopropyl and 2,2,2, trifluoroethyl.One In a embodiment, R41bbrFor ethyl.
In one embodiment, R43bbrIt is selected from: phenyl and being replaced by 1 or 2 substituent group independently selected from the following Phenyl: fluorine and chlorine.
In one embodiment, R44bbrAnd R45bbrIndependently selected from: methyl and-CH2C(O)NH2。
In one embodiment, R44bbrAnd R45bbrNitrogen connected to them is formed together: piperidyl, by 1 or 2 Independently selected from amino ,-NHCH2C(CH3)3, fluorine, chlorine and-N (CH3) cyclobutyl substituent group replace piperidyl, pyrrolidinyl With the pyrrolidinyl being optionally substituted by a hydroxyl group.
Include in formula (I) compound and the method for the present invention:
2- [(6- amino -3,5- dicyano -4- ethylpyridine -2- base) sulfanyl] -2- phenyl-acetamides；
(R)-[(6- amino -3,5- dicyano -4- ethylpyridine -2- base) sulfanyl] -2- phenyl-acetamides；
2- { [3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base] sulfanyl } -2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- { [3,5- dicyano -4- cyclopropyl -6- (4- ethyl -1,4- Diazesuberane -1- base) pyridine -2- base] sulphur Alkyl } -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- propyl -1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- { [3,5- dicyano -4- ethyl -6- (4- ethyl -1,4- Diazesuberane -1- base) pyridine -2- base] sulfane Base } -2- phenyl-acetamides；
2- { [3,5- dicyano -4- ethyl -6- (5- oxo -1,4- Diazesuberane -1- base) pyridine -2- base] sulfane Base } -2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- morpholino pyridine -2- base) sulfenyl) -2- (pyridin-4-yl) acetamide；
2- { [3,5- dicyano -4- ethyl -6- (4- methyl -3- oxypiperazin -1- base) pyridine -2- base] sulfanyl } -2- (pyridin-4-yl) acetamide；
2- [(3,5- dicyano -4- ethyl -6- { methyl [2- (morpholine -4- base) ethyl] amino } pyridine -2- base) sulfane Base] -2- phenyl-acetamides；
2- { [3,5- dicyano -4- ethyl -6- (4- propylpiperazine -1- base) pyridine -2- base] sulfanyl } -2- phenylacetyl Amine；
2- ({ 3,5- dicyano -4- ethyl -6- [4- (piperidin-4-yl) piperazine -1- base] pyridine -2- base } sulfanyl) -2- Phenyl-acetamides；
2- ({ 3,5- dicyano -4- cyclopropyl -6- [3- (hydroxymethyl) piperazine -1- base] pyridine -2- base } sulfanyl) -2- Phenyl-acetamides；
2- { [3,5- dicyano -4- cyclopropyl -6- (3- oxypiperazin -1- base) pyridine -2- base] sulfanyl } -2- phenyl second Amide；
2- ({ 3,5- dicyano -4- cyclopropyl -6- [4- (morpholine -4- base) piperidin-1-yl] pyridine -2- base } sulfanyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (2,8- diaza spiro [4.5] decyl- 8- yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；2,2,2- trifluoroacetic acid；
2- ((3,5- dicyano -4- cyclopropyl -6- (3- (dimethylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (3- methylpiperazine-1-yl) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- cyclopropyl -6- (2- (hydroxymethyl) morpholino) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- cyclopropyl -6- (2,6- thebaine generation) pyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- cyclopropyl -6- (3- (dimethylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((6- (4- (amino methyl) -4- hydroxy piperidine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (3- (methylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((6- (3- amino piperidine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- cyclopropyl -6- (dimethylamino) pyridine -2- base) sulfenyl) -2- (pyridin-4-yl) second Amide；
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (pyridin-4-yl) acetyl Amine；
2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- cyclopropyl -6- (4- (dimethylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- (pyridin-4-yl) second Amide；
2- ((3,5- dicyano -4- cyclopropyl -6- (1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (pyridin-4-yl) acetamide；
2- ((3,5- dicyano -4- cyclopropyl -6- ((R) -3- hydroxy piperidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- (3,5- dicyano -4- cyclopropyl -6- ((S) -3- hydroxy piperidine -1- base) pyridine -2- base sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- cyclopropyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (pyridin-4-yl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- ethyl piperazidine -1- base) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- (1- oxa- -6- azaspiro [3.4] octyl- 6- yl) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((6- (4- (3- aminopropyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- (1,7- diaza spiro [3.5] nonyl- 1- yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides trifluoroacetate；
2- ((3,5- dicyano -4- cyclopropyl -6- (4- (pyrrolidin-1-yl methyl) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
(R) -2- ((3,5- dicyano -6- (1,4- Diazesuberane -1- base) -4- ethylpyridine -2- base) amino) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides trifluoroacetate；
2- ((3,5- dicyano -4- ethyl -6- (2,7- diaza spiro [3.5] nonyl- 7- yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (2,6- diaza spiro [3.4] octyl- 6- yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) propionyl Amine；
2- ((3,5- dicyano -4- ethyl -6- (4- (2- oxo-imidazole alkane -1- base) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- hydroxy piperidine -1- base) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- ethyl -6- (3- oxypiperazin -1- base) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- [(6- amino -3,5- dicyano -4- cyclopropyl -2- pyridyl group) sulfanyl] -2- phenvl-acetamide；
2- ((3,5- dicyano -4- ethyl -6- (methylamino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- methoxy ethyl) (methyl) amino) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (3- methoxyl group azetidine -1- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- morpholino pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- [[6- (azetidine -1- base) -3,5- dicyano -4- ethyl -2- pyridyl group] sulfanyl] -2- phenyl-second Amide；
2- ((3,5- dicyano -4- ethyl -6- (4- oxo-piperidine -1- base) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- (1'- (2- hydroxyethyl)-[4,4'- joins piperidines] -1- base) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((3S, 5R) -3,5- lupetazin -1- base) -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((6- (8- azabicyclo [3.2.1] oct-3-yl (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (2- (hydroxymethyl) morpholino) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
(R) -2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
(R) -2- [(3,5- dicyano -4- ethyl -6- morpholino -2- pyridyl group) sulfanyl] -2- phenvl-acetamide；
N- (4- ((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- base sulfenyl) first Base) benzyl) acetamide trifluoroacetate；
2- { [3,5- dicyano -4- ethyl -6- (5- methyl-1,4- Diazesuberane -1- base) pyridine -2- base] sulfane Base } -2- phenyl-acetamides；
2- (4- (amino methyl) benzyl sulfenyl) -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -3,5- Dimethoxy nitrile；
4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) methyl) the benzylcarbamate tert-butyl ester；
4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) methyl) benzamide；
2- ((4- (amino methyl) benzyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyrrole Pyridine -3,5- dimethoxy nitrile dihydrochloride；
2- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) phenyl) acetic acid；
4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) methyl) benzoic acid；
2- (dimethylamino) -4- ethyl -6- (((6- oxo -1,6- dihydropyridine -3- base) methyl) sulfenyl) pyridine -3, 5- dimethoxy nitrile；
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) thiazol-2-yl) acetamide；
4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) methyl) benzsulfamide；
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) benzyl) acetamide；
(2- ((4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) methyl) benzyl) amino) -2- oxoethyl) t-butyl carbamate；
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) benzyl) methylsulfonamides；
2- amino-N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyrrole Pyridine -2- base) sulfenyl) methyl) benzyl) acetamide；
2- (4- amino piperidine -1- base) -6- (benzyl sulfenyl) -4- ethylpyridine -3,5- dimethoxy nitrile；
Acetic acid 4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) benzyl ester；
2- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) phenyl-acetamides；
2- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) phenyl)-N- methylacetamide；
4- ethyl -2- ((4- (hydroxymethyl) benzyl) sulfenyl) -6- (4- methyl-1,4- Diazesuberane -1- base) pyrrole Pyridine -3,5- dimethoxy nitrile；
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) benzyl) -2- hydroxyl acetamide；
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) benzyl) propionamide；
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) benzyl) isobutyramide；
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) benzyl) -3- methylbutyryl amine；
4- ethyl -2- ((4- (((2- hydroxyethyl) amino) methyl) benzyl) sulfenyl) -6- (4- methyl-1,4- diaza Cycloheptane -1- base) pyridine -3,5- dimethoxy nitrile；
N- (4- (((3,5- dicyano -6- (4- methyl-1,4- Diazesuberane -1- base) -4- (methylamino) pyridine - 2- yl) sulfenyl) methyl) benzyl) acetamide；
2- (((2- acetyl group -1,2,3,4- tetrahydroisoquinoline -6- base) methyl) sulfenyl) -6- (dimethylamino) -4- second Yl pyridines -3,5- dimethoxy nitrile；
2- ((4- cyanobenzyls) sulfenyl) -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -3,5- Dimethoxy nitrile；
2- amino-N- (1- (6- (benzyl sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl) acetyl Amine, trifluoroacetate；
2- amino-N- (1- (6- (benzyl sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl) -2- first Base propionamide, formates；
3- amino-N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyrrole Pyridine -2- base) sulfenyl) methyl) benzyl) propionamide；
(S) -2- amino-N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) Pyridine -2- base) sulfenyl) methyl) benzyl) propionamide；
(R) -2- amino-N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) Pyridine -2- base) sulfenyl) methyl) benzyl) propionamide；
1- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) benzyl) -3- ethyl carbamide；
1- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) benzyl) -3- phenylurea；
N- (4- (((3,5- dicyano -6- (4- methyl-1,4- Diazesuberane -1- base) -4- (methylsulfany) pyridine - 2- yl) sulfenyl) methyl) benzyl) acetamide；
(E) -3- (4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl) phenyl) Acrylic acid, trifluoroacetate；
N- (4- (((3,5- dicyano -4- ethyl -6- ((2- hydroxyethyl) (methyl) amino) pyridine -2- base) sulfenyl) first Base) benzyl) acetamide；
4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) methyl)-N- methyl benzenesulfonamide；
N- (4- (((3,5- dicyano -4- ethyoxyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) methyl) benzyl) acetamide；
2- ({ 3,5- dicyano -4- ethyl -6- [4- (2- methoxy ethyl) -1,4- Diazesuberane -1- base] pyridine - 2- yl } sulfanyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxypropyl) -1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- [4- (6- { [carbamoyl (phenyl) methyl] sulfanyl } -3,5- dicyano -4- ethylpyridine -2- base) -1, 4- Diazesuberane -1- base] methyl acetate；
2- { [3,5- dicyano -4- cyclopropyl -6- (4- methyl -5- oxo -1,4- Diazesuberane -1- base) pyridine - 2- yl] sulfanyl } -2- phenyl-acetamides；
2- { [3,5- dicyano -4- cyclopropyl -6- (5- oxo -1,4- Diazesuberane -1- base) pyridine -2- base] sulphur Alkyl } -2- phenyl-acetamides；
2- { [3,5- dicyano -4- ethyl -6- (4- methyl -5- oxo -1,4- Diazesuberane -1- base) pyridine -2- Base] sulfanyl } -2- phenyl-acetamides；
2- { [3,5- dicyano -6- (1,4- Diazesuberane -1- base) -4- ethylpyridine -2- base] sulfanyl } -2- benzene Yl acetamide；
2- ({ 3,5- dicyano -6- [4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base] -4- (2,2,2- trifluoro Ethyl) pyridine -2- base } sulfanyl) -2- phenyl-acetamides；
(2R) -2- ({ 3,5- dicyano -4- ethyl -6- [4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base] pyrrole Pyridine -2- base } amino) -2- phenyl-acetamides；
2- ({ 6- [(3S) -3- amino-pyrrolidine -1- base] -3,5- dicyano -4- cyclopropyl pyridine -2- base } sulfanyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (2,9- diaza spiro [5.5] hendecane -9- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (hexahydro -1H- pyrrolo- [1,2-a] [1,4] diazacyclo heptantriene -2 (3H)-yl) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (2- methyl -2,9- diaza spiro [5.5] hendecane -9- base) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (2- (Cvclopropvlmethvl) -2,9- diaza spiro [5.5] hendecane -9- base) -4- ethyl Pyridine -2- base) sulfenyl) -2- phenylacetyl amine hydrochlorate；
2- ((3,5- dicyano -6- (4- (3- (dimethylamino) propyl) piperazine -1- base) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-3-yl) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；2,2,2- trifluoroacetic acid；
2- ((6- ([4,4'- joins piperidines] -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；2,2,2- trifluoroacetic acid；
2- ((6- (4- (2- amino-ethyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((6- (4- (3- aminopropyl) piperazine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (4- ((4- methylpiperazine-1-yl) methyl) piperidin-1-yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides trifluoroacetate；
2- ((6- (4- Acetylpiperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- cyclopropyl -6- (dimethylamino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- (4- chlorphenyl) -2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) acetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxyethyl) piperazine -1- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- [(3,5- dicyano -4- cyclopropyl -6- morpholino -2- pyridyl group) sulfanyl] -2- phenvl-acetamide；
2- ((6- (4- benzoyl-piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- ethyl -6- ((5S, 6S) -6- hydroxyl -1- (methyl sulphonyl) -1,8- diaza spiro [4.5] decyl- 8- yl) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4,4- difluoropiperdin -1- base) -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
(R) -2- ((3,5- dicyano -4- ethyl -6- ((R) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((6- (4- amino -4- methyl piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) acetamide 2,2,2- trifluoroacetate；
(2S) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- second Yl pyridines -2- base) piperidin-4-yl) propionamide 2,2,2- trifluoroacetate；
2- ((6- (4- (3- amino oxetanes -3- carbonyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides formates；
4- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) tetrahydro -2H- pyrans -4- formamide 2,2,2- trifluoroacetate；
2- ((6- (4- (4- amino tetrahydro -2H- pyrans -4- carbonyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine - 2- yl) sulfenyl) -2- phenyl-acetamides 2,2,2- trifluoroacetate；
2- ((3,5- dicyano -6- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base) -4-methoxypyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((6- ((2- amino-ethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide 2,2,2- trifluoroacetate；
2- ((6- ((2- amino -2- oxoethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (3- hydroxy azetidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((2- hydroxyethyl) (methyl) amino) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) -2- methyl propanamide；
2- ((6- (4- (2- amino ethoxy) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides 2,2,2- trifluoroacetate；
2- ((3,5- dicyano -4- ethyl -6- (3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxyl-oxethyl) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
N- (4- (((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) methyl) benzyl Base) acetamide 2,2,2- trifluoroacetate；With
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (piperidin-4-yl) acetyl Amine；
Or its pharmaceutically acceptable salt or prodrug.
The prodrug of formula (I) of the present invention is:
Biphosphate 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) pyrrolidin-3-yl ester；
Biphosphate 2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) (methyl) amino) ethyl ester；
Biphosphate 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) azetidine -3- base ester；
(2S) -2- amino -3 Methylbutanoic acid 2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- Dicyano -4- ethylpyridine -2- base) piperidin-4-yl) oxygroup) ethyl ester；
Biphosphate 2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) oxygroup) ethyl ester；
Biphosphate 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) piperidin-4-yl ester；
Or its pharmaceutically acceptable salt.
Suitably, new formula (IVa) compound of the invention is selected from:
2- { [3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base] sulfanyl } -2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- { [3,5- dicyano -4- cyclopropyl -6- (4- ethyl -1,4- Diazesuberane -1- base) pyridine -2- base] sulphur Alkyl } -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- propyl -1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- { [3,5- dicyano -4- ethyl -6- (4- ethyl -1,4- Diazesuberane -1- base) pyridine -2- base] sulfane Base } -2- phenyl-acetamides；
2- { [3,5- dicyano -4- ethyl -6- (5- oxo -1,4- Diazesuberane -1- base) pyridine -2- base] sulfane Base } -2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- morpholino pyridine -2- base) sulfenyl) -2- (pyridin-4-yl) acetamide；
2- { [3,5- dicyano -4- ethyl -6- (4- methyl -3- oxypiperazin -1- base) pyridine -2- base] sulfanyl } -2- (pyridin-4-yl) acetamide；
2- [(3,5- dicyano -4- ethyl -6- { methyl [2- (morpholine -4- base) ethyl] amino } pyridine -2- base) sulfane Base] -2- phenyl-acetamides；
2- { [3,5- dicyano -4- ethyl -6- (4- propylpiperazine -1- base) pyridine -2- base] sulfanyl } -2- phenylacetyl Amine；
2- ({ 3,5- dicyano -4- ethyl -6- [4- (piperidin-4-yl) piperazine -1- base] pyridine -2- base } sulfanyl) -2- Phenyl-acetamides；
2- ({ 3,5- dicyano -4- cyclopropyl -6- [3- (hydroxymethyl) piperazine -1- base] pyridine -2- base } sulfanyl) -2- Phenyl-acetamides；
2- { [3,5- dicyano -4- cyclopropyl -6- (3- oxypiperazin -1- base) pyridine -2- base] sulfanyl } -2- phenyl second Amide；
2- ({ 3,5- dicyano -4- cyclopropyl -6- [4- (morpholine -4- base) piperidin-1-yl] pyridine -2- base } sulfanyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (2,8- diaza spiro [4.5] decyl- 8- yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；2,2,2- trifluoroacetic acid；
2- ((3,5- dicyano -4- cyclopropyl -6- (3- (dimethylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (3- methylpiperazine-1-yl) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- cyclopropyl -6- (2- (hydroxymethyl) morpholino) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- cyclopropyl -6- (2,6- thebaine generation) pyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- cyclopropyl -6- (3- (dimethylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((6- (4- (amino methyl) -4- hydroxy piperidine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (3- (methylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((6- (3- amino piperidine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- cyclopropyl -6- (dimethylamino) pyridine -2- base) sulfenyl) -2- (pyridin-4-yl) second Amide；
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (pyridin-4-yl) acetyl Amine；
2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- cyclopropyl -6- (4- (dimethylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- (pyridin-4-yl) second Amide；
2- ((3,5- dicyano -4- cyclopropyl -6- (1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (pyridin-4-yl) acetamide；
2- ((3,5- dicyano -4- cyclopropyl -6- ((R) -3- hydroxy piperidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- (3,5- dicyano -4- cyclopropyl -6- ((S) -3- hydroxy piperidine -1- base) pyridine -2- base sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- cyclopropyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (pyridin-4-yl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- ethyl piperazidine -1- base) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- (1- oxa- -6- azaspiro [3.4] octyl- 6- yl) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((6- (4- (3- aminopropyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- (1,7- diaza spiro [3.5] nonyl- 1- yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides trifluoroacetate；
2- ((3,5- dicyano -4- cyclopropyl -6- (4- (pyrrolidin-1-yl methyl) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
(R) -2- ((3,5- dicyano -6- (1,4- Diazesuberane -1- base) -4- ethylpyridine -2- base) amino) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides trifluoroacetate；
2- ((3,5- dicyano -4- ethyl -6- (2,7- diaza spiro [3.5] nonyl- 7- yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (2,6- diaza spiro [3.4] octyl- 6- yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) propionyl Amine；
2- ((3,5- dicyano -4- ethyl -6- (4- (2- oxo-imidazole alkane -1- base) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- hydroxy piperidine -1- base) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- ethyl -6- (3- oxypiperazin -1- base) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- ((2- methoxy ethyl) (methyl) amino) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (3- methoxyl group azetidine -1- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- morpholino pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- [[6- (azetidine -1- base) -3,5- dicyano -4- ethyl -2- pyridyl group] sulfanyl] -2- phenyl-second Amide；
2- ((3,5- dicyano -4- ethyl -6- (4- oxo-piperidine -1- base) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- (1'- (2- hydroxyethyl)-[4,4'- joins piperidines] -1- base) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((3S, 5R) -3,5- lupetazin -1- base) -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((6- (8- azabicyclo [3.2.1] oct-3-yl (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (2- (hydroxymethyl) morpholino) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
(R) -2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
(R) -2- [(3,5- dicyano -4- ethyl -6- morpholino -2- pyridyl group) sulfanyl] -2- phenvl-acetamide；
N- (4- ((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- base sulfenyl) first Base) benzyl) acetamide trifluoroacetate；
2- { [3,5- dicyano -4- ethyl -6- (5- methyl-1,4- Diazesuberane -1- base) pyridine -2- base] sulfane Base } -2- phenyl-acetamides；
2- (4- (amino methyl) benzyl sulfenyl) -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -3,5- Dimethoxy nitrile；
4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) methyl) the benzylcarbamate tert-butyl ester；
4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) methyl) benzamide；
2- ((4- (amino methyl) benzyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyrrole Pyridine -3,5- dimethoxy nitrile dihydrochloride；
2- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) phenyl) acetic acid；
4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) methyl) benzoic acid；
2- (dimethylamino) -4- ethyl -6- (((6- oxo -1,6- dihydropyridine -3- base) methyl) sulfenyl) pyridine -3, 5- dimethoxy nitrile；
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) thiazol-2-yl) acetamide；
4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) methyl) benzsulfamide；
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) benzyl) acetamide；
(2- ((4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) methyl) benzyl) amino) -2- oxoethyl) t-butyl carbamate；
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) benzyl) methylsulfonamides；
2- amino-N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyrrole Pyridine -2- base) sulfenyl) methyl) benzyl) acetamide；
2- (4- amino piperidine -1- base) -6- (benzyl sulfenyl) -4- ethylpyridine -3,5- dimethoxy nitrile；
Acetic acid 4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) benzyl ester；
2- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) phenyl-acetamides；
2- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) phenyl)-N- methylacetamide；
4- ethyl -2- ((4- (hydroxymethyl) benzyl) sulfenyl) -6- (4- methyl-1,4- Diazesuberane -1- base) pyrrole Pyridine -3,5- dimethoxy nitrile；
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) benzyl) -2- hydroxyl acetamide；
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) benzyl) propionamide；
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) benzyl) isobutyramide；
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) benzyl) -3- methylbutyryl amine；
4- ethyl -2- ((4- (((2- hydroxyethyl) amino) methyl) benzyl) sulfenyl) -6- (4- methyl-1,4- diaza Cycloheptane -1- base) pyridine -3,5- dimethoxy nitrile；
N- (4- (((3,5- dicyano -6- (4- methyl-1,4- Diazesuberane -1- base) -4- (methylamino) pyridine - 2- yl) sulfenyl) methyl) benzyl) acetamide；
2- (((2- acetyl group -1,2,3,4- tetrahydroisoquinoline -6- base) methyl) sulfenyl) -6- (dimethylamino) -4- second Yl pyridines -3,5- dimethoxy nitrile；
2- ((4- cyanobenzyls) sulfenyl) -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -3,5- Dimethoxy nitrile；
2- amino-N- (1- (6- (benzyl sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl) acetyl Amine, trifluoroacetate；
2- amino-N- (1- (6- (benzyl sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl) -2- first Base propionamide, formates；
3- amino-N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyrrole Pyridine -2- base) sulfenyl) methyl) benzyl) propionamide；
(S) -2- amino-N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) Pyridine -2- base) sulfenyl) methyl) benzyl) propionamide；
(R) -2- amino-N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) Pyridine -2- base) sulfenyl) methyl) benzyl) propionamide；
1- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) benzyl) -3- ethyl carbamide；
1- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) benzyl) -3- phenylurea；
N- (4- (((3,5- dicyano -6- (4- methyl-1,4- Diazesuberane -1- base) -4- (methylsulfany) pyridine - 2- yl) sulfenyl) methyl) benzyl) acetamide；
(E) -3- (4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl) phenyl) Acrylic acid, trifluoroacetate；
N- (4- (((3,5- dicyano -4- ethyl -6- ((2- hydroxyethyl) (methyl) amino) pyridine -2- base) sulfenyl) first Base) benzyl) acetamide；
4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) methyl)-N- methyl benzenesulfonamide；
N- (4- (((3,5- dicyano -4- ethyoxyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) methyl) benzyl) acetamide；
2- ({ 3,5- dicyano -4- ethyl -6- [4- (2- methoxy ethyl) -1,4- Diazesuberane -1- base] pyridine - 2- yl } sulfanyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxypropyl) -1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- [4- (6- { [carbamoyl (phenyl) methyl] sulfanyl } -3,5- dicyano -4- ethylpyridine -2- base) -1, 4- Diazesuberane -1- base] methyl acetate；
2- { [3,5- dicyano -4- cyclopropyl -6- (4- methyl -5- oxo -1,4- Diazesuberane -1- base) pyridine - 2- yl] sulfanyl } -2- phenyl-acetamides；
2- { [3,5- dicyano -4- cyclopropyl -6- (5- oxo -1,4- Diazesuberane -1- base) pyridine -2- base] sulphur Alkyl } -2- phenyl-acetamides；
2- { [3,5- dicyano -4- ethyl -6- (4- methyl -5- oxo -1,4- Diazesuberane -1- base) pyridine -2- Base] sulfanyl } -2- phenyl-acetamides；
2- { [3,5- dicyano -6- (1,4- Diazesuberane -1- base) -4- ethylpyridine -2- base] sulfanyl } -2- benzene Yl acetamide；
2- ({ 3,5- dicyano -6- [4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base] -4- (2,2,2- trifluoro Ethyl) pyridine -2- base } sulfanyl) -2- phenyl-acetamides；
(2R) -2- ({ 3,5- dicyano -4- ethyl -6- [4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base] pyrrole Pyridine -2- base } amino) -2- phenyl-acetamides；
2- ({ 6- [(3S) -3- amino-pyrrolidine -1- base] -3,5- dicyano -4- cyclopropyl pyridine -2- base } sulfanyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (2,9- diaza spiro [5.5] hendecane -9- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (hexahydro -1H- pyrrolo- [1,2-a] [1,4] diazacyclo heptantriene -2 (3H)-yl) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (2- methyl -2,9- diaza spiro [5.5] hendecane -9- base) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (2- (Cvclopropvlmethvl) -2,9- diaza spiro [5.5] hendecane -9- base) -4- ethyl Pyridine -2- base) sulfenyl) -2- phenylacetyl amine hydrochlorate；
2- ((3,5- dicyano -6- (4- (3- (dimethylamino) propyl) piperazine -1- base) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-3-yl) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；2,2,2- trifluoroacetic acid；
2- ((6- ([4,4'- joins piperidines] -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；2,2,2- trifluoroacetic acid；
2- ((6- (4- (2- amino-ethyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((6- (4- (3- aminopropyl) piperazine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (4- ((4- methylpiperazine-1-yl) methyl) piperidin-1-yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides trifluoroacetate；
2- ((6- (4- Acetylpiperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- cyclopropyl -6- (dimethylamino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- (4- chlorphenyl) -2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) acetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxyethyl) piperazine -1- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- [(3,5- dicyano -4- cyclopropyl -6- morpholino -2- pyridyl group) sulfanyl] -2- phenvl-acetamide；
2- ((6- (4- benzoyl-piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- ethyl -6- ((5S, 6S) -6- hydroxyl -1- (methyl sulphonyl) -1,8- diaza spiro [4.5] decyl- 8- yl) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4,4- difluoropiperdin -1- base) -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
(R) -2- ((3,5- dicyano -4- ethyl -6- ((R) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((6- (4- amino -4- methyl piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) acetamide 2,2,2- trifluoroacetate；
(2S) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- second Yl pyridines -2- base) piperidin-4-yl) propionamide 2,2,2- trifluoroacetate；
2- ((6- (4- (3- amino oxetanes -3- carbonyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides formates；
4- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) tetrahydro -2H- pyrans -4- formamide 2,2,2- trifluoroacetate；
2- ((6- (4- (4- amino tetrahydro -2H- pyrans -4- carbonyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine - 2- yl) sulfenyl) -2- phenyl-acetamides 2,2,2- trifluoroacetate；
2- ((3,5- dicyano -6- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base) -4-methoxypyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((6- ((2- amino-ethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide 2,2,2- trifluoroacetate；
2- ((6- ((2- amino -2- oxoethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (3- hydroxy azetidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((2- hydroxyethyl) (methyl) amino) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) -2- methyl propanamide；
2- ((6- (4- (2- amino ethoxy) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides 2,2,2- trifluoroacetate；
2- ((3,5- dicyano -4- ethyl -6- (3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxyl-oxethyl) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
N- (4- (((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) methyl) benzyl Base) acetamide 2,2,2- trifluoroacetate；With
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (piperidin-4-yl) acetyl Amine；
Or its pharmaceutically acceptable salt or prodrug.
The prodrug of formula (IVa) is:
Biphosphate 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) pyrrolidin-3-yl ester；
Biphosphate 2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) (methyl) amino) ethyl ester；
Biphosphate 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) azetidine -3- base ester；
(2S) -2- amino -3 Methylbutanoic acid 2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- Dicyano -4- ethylpyridine -2- base) piperidin-4-yl) oxygroup) ethyl ester；
Biphosphate 2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) oxygroup) ethyl ester；
Biphosphate 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) piperidin-4-yl ester；
Or its pharmaceutically acceptable salt.
Primary amide:
Include in formula (Ibr) compound and the method for the present invention:
2- [(6- amino -3,5- dicyano -4- ethylpyridine -2- base) sulfanyl] -2- phenyl-acetamides；
(R)-[(6- amino -3,5- dicyano -4- ethylpyridine -2- base) sulfanyl] -2- phenyl-acetamides；
2- { [3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base] sulfanyl } -2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- { [3,5- dicyano -4- cyclopropyl -6- (4- ethyl -1,4- Diazesuberane -1- base) pyridine -2- base] sulphur Alkyl } -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- propyl -1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- { [3,5- dicyano -4- ethyl -6- (4- ethyl -1,4- Diazesuberane -1- base) pyridine -2- base] sulfane Base } -2- phenyl-acetamides；
2- { [3,5- dicyano -4- ethyl -6- (5- oxo -1,4- Diazesuberane -1- base) pyridine -2- base] sulfane Base } -2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- morpholino pyridine -2- base) sulfenyl) -2- (pyridin-4-yl) acetamide；
2- { [3,5- dicyano -4- ethyl -6- (4- methyl -3- oxypiperazin -1- base) pyridine -2- base] sulfanyl } -2- (pyridin-4-yl) acetamide；
2- [(3,5- dicyano -4- ethyl -6- { methyl [2- (morpholine -4- base) ethyl] amino } pyridine -2- base) sulfane Base] -2- phenyl-acetamides；
2- { [3,5- dicyano -4- ethyl -6- (4- propylpiperazine -1- base) pyridine -2- base] sulfanyl } -2- phenylacetyl Amine；
2- ({ 3,5- dicyano -4- ethyl -6- [4- (piperidin-4-yl) piperazine -1- base] pyridine -2- base } sulfanyl) -2- Phenyl-acetamides；
2- ({ 3,5- dicyano -4- cyclopropyl -6- [3- (hydroxymethyl) piperazine -1- base] pyridine -2- base } sulfanyl) -2- Phenyl-acetamides；
2- { [3,5- dicyano -4- cyclopropyl -6- (3- oxypiperazin -1- base) pyridine -2- base] sulfanyl } -2- phenyl second Amide；
2- ({ 3,5- dicyano -4- cyclopropyl -6- [4- (morpholine -4- base) piperidin-1-yl] pyridine -2- base } sulfanyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (2,8- diaza spiro [4.5] decyl- 8- yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (3- (dimethylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (3- methylpiperazine-1-yl) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- cyclopropyl -6- (2- (hydroxymethyl) morpholino) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- cyclopropyl -6- (2,6- thebaine generation) pyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- cyclopropyl -6- (3- (dimethylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((6- (4- (amino methyl) -4- hydroxy piperidine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (3- (methylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((6- (3- amino piperidine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- cyclopropyl -6- (dimethylamino) pyridine -2- base) sulfenyl) -2- (pyridin-4-yl) second Amide；
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (pyridin-4-yl) acetyl Amine；
2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- cyclopropyl -6- (4- (dimethylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- (pyridin-4-yl) second Amide；
2- ((3,5- dicyano -4- cyclopropyl -6- (1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (pyridin-4-yl) acetamide；
2- ((3,5- dicyano -4- cyclopropyl -6- ((R) -3- hydroxy piperidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- (3,5- dicyano -4- cyclopropyl -6- ((S) -3- hydroxy piperidine -1- base) pyridine -2- base sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- cyclopropyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (pyridin-4-yl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- ethyl piperazidine -1- base) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- (1- oxa- -6- azaspiro [3.4] octyl- 6- yl) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((6- (4- (3- aminopropyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- (1,7- diaza spiro [3.5] nonyl- 1- yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (4- (pyrrolidin-1-yl methyl) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
(R) -2- ((3,5- dicyano -6- (1,4- Diazesuberane -1- base) -4- ethylpyridine -2- base) amino) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (2,7- diaza spiro [3.5] nonyl- 7- yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (2,6- diaza spiro [3.4] octyl- 6- yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) propionyl Amine；
2- ((3,5- dicyano -4- ethyl -6- (4- (2- oxo-imidazole alkane -1- base) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- hydroxy piperidine -1- base) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- ethyl -6- (3- oxypiperazin -1- base) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- [(6- amino -3,5- dicyano -4- cyclopropyl -2- pyridyl group) sulfanyl] -2- phenvl-acetamide；
2- ((3,5- dicyano -4- ethyl -6- (methylamino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- methoxy ethyl) (methyl) amino) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (3- methoxyl group azetidine -1- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- morpholino pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- [[6- (azetidine -1- base) -3,5- dicyano -4- ethyl -2- pyridyl group] sulfanyl] -2- phenyl-second Amide；
2- ((3,5- dicyano -4- ethyl -6- (4- oxo-piperidine -1- base) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- (1'- (2- hydroxyethyl)-[4,4'- joins piperidines] -1- base) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((3S, 5R) -3,5- lupetazin -1- base) -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((6- (8- azabicyclo [3.2.1] oct-3-yl (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (2- (hydroxymethyl) morpholino) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
(R) -2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
(R) -2- [(3,5- dicyano -4- ethyl -6- morpholino -2- pyridyl group) sulfanyl] -2- phenvl-acetamide；
2- { [3,5- dicyano -4- ethyl -6- (5- methyl-1,4- Diazesuberane -1- base) pyridine -2- base] sulfane Base } -2- phenyl-acetamides；
2- ({ 3,5- dicyano -4- ethyl -6- [4- (2- methoxy ethyl) -1,4- Diazesuberane -1- base] pyridine - 2- yl } sulfanyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxypropyl) -1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- [4- (6- { [carbamoyl (phenyl) methyl] sulfanyl } -3,5- dicyano -4- ethylpyridine -2- base) -1, 4- Diazesuberane -1- base] methyl acetate；
2- { [3,5- dicyano -4- cyclopropyl -6- (4- methyl -5- oxo -1,4- Diazesuberane -1- base) pyridine - 2- yl] sulfanyl } -2- phenyl-acetamides；
2- { [3,5- dicyano -4- cyclopropyl -6- (5- oxo -1,4- Diazesuberane -1- base) pyridine -2- base] sulphur Alkyl } -2- phenyl-acetamides；
2- { [3,5- dicyano -4- ethyl -6- (4- methyl -5- oxo -1,4- Diazesuberane -1- base) pyridine -2- Base] sulfanyl } -2- phenyl-acetamides；
2- { [3,5- dicyano -6- (1,4- Diazesuberane -1- base) -4- ethylpyridine -2- base] sulfanyl } -2- benzene Yl acetamide；
2- ({ 3,5- dicyano -6- [4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base] -4- (2,2,2- trifluoro Ethyl) pyridine -2- base } sulfanyl) -2- phenyl-acetamides；
(2R) -2- ({ 3,5- dicyano -4- ethyl -6- [4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base] pyrrole Pyridine -2- base } amino) -2- phenyl-acetamides；
2- ({ 6- [(3S) -3- amino-pyrrolidine -1- base] -3,5- dicyano -4- cyclopropyl pyridine -2- base } sulfanyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (2,9- diaza spiro [5.5] hendecane -9- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (hexahydro -1H- pyrrolo- [1,2-a] [1,4] diazacyclo heptantriene -2 (3H)-yl) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (2- methyl -2,9- diaza spiro [5.5] hendecane -9- base) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (2- (Cvclopropvlmethvl) -2,9- diaza spiro [5.5] hendecane -9- base) -4- ethyl Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- (3- (dimethylamino) propyl) piperazine -1- base) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-3-yl) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((6- ([4,4'- joins piperidines] -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((6- (4- (2- amino-ethyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((6- (4- (3- aminopropyl) piperazine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (4- ((4- methylpiperazine-1-yl) methyl) piperidin-1-yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((6- (4- Acetylpiperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- cyclopropyl -6- (dimethylamino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- (4- chlorphenyl) -2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) acetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxyethyl) piperazine -1- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- [(3,5- dicyano -4- cyclopropyl -6- morpholino -2- pyridyl group) sulfanyl] -2- phenvl-acetamide；
2- ((6- (4- benzoyl-piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- ethyl -6- ((5S, 6S) -6- hydroxyl -1- (methyl sulphonyl) -1,8- diaza spiro [4.5] decyl- 8- yl) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4,4- difluoropiperdin -1- base) -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
(R) -2- ((3,5- dicyano -4- ethyl -6- ((R) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- (furans -2- base) -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((6- (4- amino -4- methyl piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) acetamide；
(2S) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- second Yl pyridines -2- base) piperidin-4-yl) propionamide；
2- ((6- (4- (3- amino oxetanes -3- carbonyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
4- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) tetrahydro -2H- pyrans -4- formamide；
2- ((6- (4- (4- amino tetrahydro -2H- pyrans -4- carbonyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base) -4-methoxypyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((6- ((2- amino-ethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((6- ((2- amino -2- oxoethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (3- hydroxy azetidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- (3,5- dicyano -4- ethyl -6- ((2- hydroxyethyl) (methyl) amino) pyridine -2- base sulfenyl) -2- phenyl Acetamide；
2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) -2- methyl propanamide；
2- ((6- (4- (2- amino ethoxy) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
Biphosphate 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) pyrrolidin-3-yl ester；
Biphosphate 2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) (methyl) amino) ethyl ester；
Biphosphate 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) azetidine -3- base ester；
(2S) -2- amino -3 Methylbutanoic acid 2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- Dicyano -4- ethylpyridine -2- base) piperidin-4-yl) oxygroup) ethyl ester；
Biphosphate 2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) oxygroup) ethyl ester；
Biphosphate 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) piperidin-4-yl ester；
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (piperidin-4-yl) acetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- (4- (sulfonyl propyl base) piperazine -1- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (phenyl sulfonyl) piperazine -1- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((R) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- ethyl -6- (2- oxa- -6- azaspiro [3.4] octyl- 6- yl) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
(R) -2- ((3,5- dicyano -4- ethyl -6- (4- ethyl -1,4- Diazesuberane -1- base) pyridine -2- base) Amino) -2- phenyl-acetamides；
(R) -2- ((3,5- dicyano -4- ethyl -6- (4- (3- (pyrrolidin-1-yl) propyl) -1,4- diaza cycloheptyl Alkane -1- base) pyridine -2- base) amino) -2- phenyl-acetamides；
2- (3,5- dicyano -4- cyclopropyl -6- (3- hydroxy piperidine -1- base) pyridine -2- base sulfenyl) -2- phenylacetyl Amine；
2- ((the chloro- 4- ethyl -6- of 3,5- bis- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -6- (1,1- sulfur dioxide morpholino) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- ethyl -6- (methyl (2- (piperazine -1- base) ethyl) amino) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
(R) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((6- ((2- (4- (amino methyl) -4- hydroxy piperidine -1- base) ethyl) (methyl) amino) -3,5- dicyano - 4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((4- cyano -3- (1,4- Diazesuberane -1- base) -6,7- dihydro -5H- cyclopenta [c] pyridine -1- Base) sulfenyl) -2- phenyl-acetamides；
2- ((6- (4- (1H- imidazoles -1- base) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (pyridin-4-yl methyl) piperazine -1- base) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -6- (2- (dimethylamino) ethyoxyl) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine -2- Base) piperidines -3- base) amino) acetic acid；
2- ((3,5- dicyano -4- ethyl -6- (4- (oxazole -2- ylmethyl) piperazine -1- base) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((6- (4- ((1H- pyrroles -2- base) methyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (- 2 (1H)-yl of 3,4- dihydro -2,7- benzodiazine) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (pyrrole Pyridine -3- base) acetamide；
2- ((6- (4- ((1H- pyrroles -3- base) methyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (isoxazole -3- ylmethyl) piperazine -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (oxazole -5- ylmethyl) piperazine -1- base) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (isoxazole -4- ylmethyl) piperazine -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
3- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) oxetanes -3- formamide；
2- ((6- (4- ((1H- pyrazoles -4- base) methyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((6- (4- ((1H- imidazoles -5- base) methyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (1- hydroxy-2-methyl propyl- 2- yl) piperazine -1- base) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((6- (4- ((1H- imidazoles -2- base) methyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (dimethylamino) -4-methoxypyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (dimethylamino) -4- ethoxy pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyoxyl -6- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base) pyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxy-2-methyl propyl) -1,4- Diazesuberane -1- base) Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (thiazole -5- ylmethyl) piperazine -1- base) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- (4- fluorophenyl) acetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- (4- (isothiazole -4- ylmethyl) piperazine -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (4- fluorophenyl) acetyl Amine；
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (5- fluorine pyridine -2- base) Acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (furans -3- ylmethyl) piperazine -1- base) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- morpholinoethyl) sulfenyl) pyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -6- (4- methyl-1,4- Diazesuberane -1- base) -4- (methylsulfany) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((the chloro- 4- ethyl -6- of 3,5- bis- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (hexahydropyrrolo simultaneously [3,4-b] [1,4] oxazines -6 (2H)-yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (5- picoline -2- base) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (6- fluorine pyridine -2- base) acetamide；
2- ((3,5- dicyano -6- (4- (dimethylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- (4- fluorophenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (4- picoline -2- base) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (3-Methoxy Pyridine -2- base) acetamide；
2- ((3,5- dicyano -6- (4- (dimethylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- (2,4 difluorobenzene base) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- (5- fluorine pyridine -2- base) acetamide；
2- ((3,5- dicyano -4- ethyoxyl -6- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base) pyridine - 2- yl) sulfenyl) propionamide；
2- ((3,5- dicyano -6- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base) -4- propoxyl group pyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (4-methoxypyridine -2- base) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (2- methyl -2,8- diaza spiro [4.5] decyl- 8- yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- (dimethylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- (3,4- difluorophenyl) acetamide；
1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperazine Pyridine -4- formamide；
2- ((3,5- dicyano -6- ((2- (dimethylamino) ethyl) sulfenyl) -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -6- ((3S, 4R) -3,4- dihydroxy pyrrolidine -1- base) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (3- fluorine pyridine -2- base) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (5- methoxypyridine -2- base) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (1- hydroxy-2-methyl propyl- 2- yl) piperazine -1- base) pyridine -2- base) Sulfenyl) -2- (4- fluorophenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (3- (trifluoromethyl) phenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxyl-oxethyl) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (2- fluorine pyridin-3-yl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (6- fluorine pyridin-3-yl) acetamide；
3- ((6- (2- amino -2- oxo -1- phenylethyl sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (first Base) amino) propionamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (oxetanes -3- base oxygroup) piperidin-1-yl) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- ((2,2- bis-fluoro ethyls) amino) -4- methyl piperidine -1- base) -4- ethylpyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (4- (trifluoromethyl) phenyl) acetamide；
2- ((6- (4- aminopiperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((6- ((2- amino -2- oxoethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- (pyrrolo- [3,4-c] pyrazoles -5 (1H, 4H, 6H)-yl) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (5- methoxypyridine - 2- yl) acetamide；
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (5- picoline -2- Base) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (2- fluorine pyridin-4-yl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- hydroxyl -4- (hydroxymethyl) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (2- oxo -3- oxa- -1,8- diaza spiro [4.5] decyl- 8- yl) pyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((6- (4- amino -4- (hydroxymethyl) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((6- (4- (amino methyl) -4- hydroxy piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- (3- benzoylphenyl) -2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxyethyl) -1,4- diaza Cycloheptane -1- base) pyridine -2- base) sulfenyl) acetamide；
2- (4- benzoylphenyl) -2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxyethyl) -1,4- diaza Cycloheptane -1- base) pyridine -2- base) sulfenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (2- picoline -4- base) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (3- (pyrrolidin-1-yl) phenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (3- fluorine pyridin-4-yl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (2,5- difluoro pyridine -4- base) acetamide；
2- ((3,5- dicyano -6- (4- (2,5- dioxoimidazolidin -1- base) piperidin-1-yl) -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
4- amino -1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) piperidines -4- formamide；
2- ((3,5- dicyano -6- (4- (2,5- dioxo pyrrolidin -1- base) piperidin-1-yl) -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides (isomers 1)；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides (isomers 2)；
2- ((3,5- dicyano -4- ethyl -6- (2- oxo -1- oxa- -3,8- diaza spiro [4.5] decyl- 8- yl) pyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) -4- Hydroxy piperidine -4- formamide；
Carbamic acid 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) azetidine -3- base ester；
2- ((3,5- dicyano -6- (4- (2,4- dioxo oxazolidine -3- base) piperidin-1-yl) -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
3- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (first Base) amino) -2- hydroxy-2-methyl propionamide；
2- ((3,5- dicyano -4- ethyl -6- (3- (hydroxymethyl) azetidine -1- base) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- (3,5- dicyano -4- ethyl -6- (piperazine -1- base) pyridine -2- base sulfenyl) -2- (thiene-3-yl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (5- picoline -3- base) acetamide；
2- ((6- (4- (3- amino -2- oxo-pyrrolidine -1- base) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
(2S) -2- amino -3 Methylbutanoic acid 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyan Base -4- ethylpyridine -2- base) piperidin-4-yl ester；
(2S) -2- amino -3 Methylbutanoic acid 2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyan Base -4- ethylpyridine -2- base) (methyl) amino) ethyl ester；
2,2'- ((3,5- dicyano -4- ethylpyridine -2,6- diyl) bis- (sulfane diyls)) bis- (2- phenyl-acetamides)；
(2S) -2- amino -3 Methylbutanoic acid (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyan Base-4-ethylpyridine-2- base) azetidine-3- base) methyl ester；
2- ((6- (3- aminoazetidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- ethyl -6- picoline -2- base) sulfenyl) -2- phenyl-acetamides；
N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) Piperidin-4-yl) -2- hydroxyl acetamide；
N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) Azetidine -3- base) -2- hydroxyl acetamide；
2- ((3- cyano -4- ethyl -5- methyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (5- methyl -2,5- diazabicyclo [2.2.1] hept- 2- yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (2- (pyrrolidin-1-yl) ethyl) piperazine -1- base) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides -2-d；
(R) -2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides - 2-d；
2- ((6- (4- (4- benzoyl bromide) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- cyano piperidine -1- base) -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
(S) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((6- (4- amino -4- methyl piperidine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (pyrrole Pyridine -2- base) acetamide；
2- ((3,5- bis- chloro- 4- ethyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
(1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperazine Pyridine -4- base) t-butyl carbamate；
2- ((6- (3- (2- amino -2- oxoethyl) azetidine -1- base) -3,5- dicyano -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
(2R) -2- amino -3 Methylbutanoic acid 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyan Base -4- ethylpyridine -2- base) azetidine -3- base ester；
2- ((3,5- dicyano -4- ethyl -6- (methyl ((5- oxo -4,5- dihydro -1H-1,2,4- triazole -3- base) first Base) amino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((6- (((4H-1,2,4- triazole -3- base) methyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyoxyl -6- picoline -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4,6- parvoline -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((6- ((2- (4H-1,2,4- triazole-4-yl) ethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((6- (((1H- pyrazole-3-yl) methyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (6,7- dihydro -1H- [1,2,3] triazol [4,5-c] pyridine -5 (4H)-yl) -4- second Yl pyridines -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((6- (((1H- imidazoles -2- base) methyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((6- (((1H- imidazoles -5- base) methyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
(2R) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- second Yl pyridines -2- base) piperidin-4-yl) propionamide；
4- (2- amino -1- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine - 2- yl) sulfenyl) -2- oxoethyl) benzamide；
2- ((3,5- dicyano -4- cyclopropyl -6- (3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- ethyl -6- (3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
(2R) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ring PropyIpyridine -2- base) piperidin-4-yl) propionamide；
2- ((6- ((2- amino-ethyl) (methyl) amino) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyrrole Pyridine -2- base) piperidin-4-yl) -2- methyl propanamide；
4- (2- amino -1- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- oxo Ethyl) benzamide；
2- (6- (4- amino piperidine -1- base) -3- cyano -4- ethyl -5- picoline -2- base sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (4- (N- Methylsulfamoyl) phenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (the fluoro- 1,4- Diazesuberane -1- base of 6-) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((6- (4- amino -3,3- difluoropiperdin -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
(1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) -3, 3- difluoropiperdin -4- base) t-butyl carbamate；
2- ((3,5- dicyano -4- cyclopropyl -6- ((2- hydroxyethyl) (methyl) amino) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (3- hydroxy azetidine -1- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) pyrroles Alkane -3- formamide；
2- ((6- ((3- aminopropyl) (methyl) amino) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- ((2- (3- hydroxy azetidine -1- base) -2- oxoethyl) (first Base) amino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((6- (4- ((2- amino -2- oxoethyl) amino) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((6- ((2- amino -2- oxoethyl) (methyl) amino) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
Carbamic acid 2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyrrole Pyridine -2- base) (methyl) amino) ethyl ester；
(2R) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- second Yl pyridines -2- base) piperidin-4-yl) -3- hydroxypropanamide；
(2S) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- second Yl pyridines -2- base) piperidin-4-yl) -3- hydroxypropanamide；
2- (4- (2- amino -2- oxoethyl) phenyl) -2- (3,5- dicyano -4- ethyl -6- (4- methyl-1,4- phenodiazine Trioxepane -1- base) pyridine -2- base sulfenyl) acetamide；
2- (4- (2- amino -2- oxoethyl) phenyl) -2- (3,5- dicyano -6- (dimethylamino) -4- ethyl pyrrole Pyridine -2- base sulfenyl) acetamide；
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (4- (N- methyl ammonia sulphur Acyl group) phenyl) acetamide；
2- ((3,5- dicyano -6- (dimethylamino-d6) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
(R) -2- ((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
(R) -2- ((3,5- dicyano -6- (4- (dimethylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- (3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base sulfenyl) -2- (3- (2- (dimethylamino Base) ethyoxyl) phenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (neopentyl amino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- (4- fluorophenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (the fluoro- 4- of 3- (neopentyl amino) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- (4- (fluoroform Base) phenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
(R) -2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((6- ((2- amino -2- oxoethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；(single enantiomer)
Biphosphate (3S) -1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl Pyridine -2- base) pyrrolidin-3-yl ester；
Biphosphate (3R) -1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl Pyridine -2- base) pyrrolidin-3-yl ester；
Biphosphate (S) -1- (6- (((S) -2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- second Yl pyridines -2- base) pyrrolidin-3-yl ester；
Biphosphate (S) -1- (6- (((R) -2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- second Yl pyridines -2- base) pyrrolidin-3-yl ester；
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (3- (solutions of dimethyl phosphoryl Base) phenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (3- (solutions of dimethyl phosphoryl base) phenyl) acetamide；
Biphosphate (R) -2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl Pyridine -2- base) (methyl) amino) ethyl ester；
(R) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (4- methoxyphenyl) acetamide；
(R) -2- (4- chlorphenyl) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine - 2- yl) sulfenyl) acetamide；
(R) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (4- fluorophenyl) acetamide；
Biphosphate (S) -1- (6- (((R) -2- amino -1- (4- fluorophenyl) -2- oxoethyl) sulfenyl) -3,5- dicyan Base -4- ethylpyridine -2- base) pyrrolidin-3-yl ester；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (4- Fluorophenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (2, 6- difluorophenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (2, 3- difluorophenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (2, 4- difluorophenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- ((S) -2- (hydroxymethyl) pyrrolidin-1-yl) piperidin-1-yl) pyrrole Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((2- hydroxyethyl) (methyl) amino) piperidin-1-yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((2- hydroxy-2-methyl propyl) (methyl) amino) piperidin-1-yl) Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-1-yl methyl) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((2- methoxyl group -2- methyl-propyl) amino) piperidin-1-yl) pyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((2- hydroxy-2-methyl propyl) amino) piperidin-1-yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- (Cyclobutylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (((3- methy oxetane -3- base) methyl) amino) piperidines -1- Base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((R) -2- methylpyrrolidin- 1- yl) piperidin-1-yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- ((2R, 5S) -2,5- dimethyl pyrrolidine -1- base) piperidin-1-yl) -4- ethyl Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((S) -2- methylpyrrolidin- 1- yl) piperidin-1-yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- (cyclobutyl (methyl) amino) piperidin-1-yl) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- (6- (4- (benzylamino) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- ethyl -6- (4- (((6- methoxypyridine -2- base) methyl) amino) piperidin-1-yl) Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((S) -3- fluoropyrrolidine -1- base) piperidin-1-yl) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (methyl (2- ((R) -2- methylpyrrolidin- 1- yl) ethyl) amino) pyrrole Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((R) -3- fluoropyrrolidine -1- base) piperidin-1-yl) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- ((2S, 5S) -2,5- dimethyl pyrrolidine -1- base) piperidin-1-yl) -4- ethyl Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (methyl (2- ((S) -2- methylpyrrolidin- 1- yl) ethyl) amino) pyrrole Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((R) -2- (hydroxymethyl) pyrrolidin-1-yl) piperidin-1-yl) pyrrole Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- (dimethylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- (4- fluorophenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (((1- methyl-cyclobutyl) methyl) amino) piperidin-1-yl) pyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (((6- methoxypyridine -3- base) methyl) amino) piperidin-1-yl) Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- (3,5- dicyano -4- ethyl -6- ((2- (ethylamino) ethyl) (methyl) amino) pyridine -2- base sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((4- methylpiperazine-1-yl) methyl) piperidin-1-yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (methyl (2- (methylamino) ethyl) amino) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- ((2R, 5R) -2,5- dimethyl pyrrolidine -1- base) piperidin-1-yl) -4- ethyl Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (((1- methylcyclopropyl groups) methyl) amino) piperidin-1-yl) pyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((4- luorobenzyl) amino) piperidin-1-yl) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((S) -2- (hydroxymethyl) pyrrolidin-1-yl) ethyl) (methyl) Amino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- (3,5- dicyano -6- ((2- ((2S, 5R) -2,5- dimethyl pyrrolidine -1- base) ethyl) (methyl) amino) - 4- ethylpyridine -2- base sulfenyl) -2- phenyl-acetamides；
2- ((6- ((2- (azepan -1- base) ethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (methyl (2- (piperidin-1-yl) ethyl) amino) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((R) -2- (hydroxymethyl) pyrrolidin-1-yl) ethyl) (methyl) Amino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- (3,5- dicyano -4- ethyl -6- ((2- (ethyl (methyl) amino) ethyl) (methyl) amino) pyridine -2- base Sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((2- ((2R, 5R) -2,5- dimethyl pyrrolidine -1- base) ethyl) (methyl) amino) - 4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- (3,5- dicyano -4- ethyl -6- ((2- ((S) -3- hydroxyl pyrrolidine -1- base) ethyl) (methyl) amino) pyrrole Pyridine -2- base sulfenyl) -2- phenyl-acetamides；
2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) Piperidin-4-yl) amino) -2 Methylpropionic acid methyl esters；
2- ((3,5- dicyano -4- ethyl -6- (methyl (2- (neopentyl amino) ethyl) amino) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- (3,5- dicyano -4- ethyl -6- (methyl (2- (1- methylcyclopropyl groups amino) ethyl) amino) pyridine -2- base Sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((2- ((2S, 5S) -2,5- dimethyl pyrrolidine -1- base) ethyl) (methyl) amino) - 4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((2- methoxy ethyl) amino) ethyl) (methyl) amino) pyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((2- methoxyl group -2- methyl-propyl) (methyl) amino) piperidines -1- Base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((2- (dimethylamino) ethyl) (methyl) amino) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- (3,5- dicyano -4- ethyl -6- ((2- ((R) -3- hydroxyl pyrrolidine -1- base) ethyl) (methyl) amino) pyrrole Pyridine -2- base sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((2- fluoro ethyl) amino) ethyl) (methyl) amino) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- (3,3- difluoropyrrolidin -1- base) piperidin-1-yl) -4- ethylpyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) Piperidin-4-yl) amino) acetic acid；
2- ((6- ((3- Aminocyclobutyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
(R) -2- (3,5- dicyano -4- ethyl -6- (methyl ((R)-tetrahydrofuran -3- base) amino) pyridine -2- base sulphur Base) -2- phenyl-acetamides；
(S) -2- (3,5- dicyano -4- ethyl -6- (methyl ((R)-tetrahydrofuran -3- base) amino) pyridine -2- base sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- morpholino piperidin-1-yl) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxyethyl) -3- oxypiperazin -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- (4- fluorophenyl) acetamide；
(R) -2- ((6- ((3S, 4R) -4- amino -3- fluorine resources -1- base) -3,5- dicyano -4- ethylpyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (3- fluoro- 4- (methylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
Rel-2- ((6- (trans-) -4- amino -3- fluorine resources -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
(R) -2- ((6- ((3R, 4S) -4- amino -3- fluorine resources -1- base) -3,5- dicyano -4- ethylpyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (the fluoro- 4- of 3- ((2- methoxy ethyl) amino) piperidin-1-yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (methyl (2- (pyrrolidin-1-yl) ethyl) amino) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (3- ((dimethylamino) methyl) pyrrolidin-1-yl) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((2- hydroxy-2-methyl propyl) amino) piperidin-1-yl) pyridine -2- Base) sulfenyl) -2- (4- fluorophenyl) acetamide；
(R) -2- ((6- ((3S, 4R) -4- amino -3- hydroxy piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((2- (diethylamino) ethyl) (methyl) amino) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((2- ((R) -3- (dimethylamino) pyrrolidin-1-yl) ethyl) (methyl) amino) - 4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((2- ((S) -3- (dimethylamino) pyrrolidin-1-yl) ethyl) (methyl) amino) - 4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
(R) -2- ((6- ((3R, 4R) -4- amino -3- fluorine resources -1- base) -3,5- dicyano -4- ethylpyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
(R) -2- ((6- ((3S, 4S) -4- amino -3- fluorine resources -1- base) -3,5- dicyano -4- ethylpyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (3- (methylamino) pyrrolidin-1-yl) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- (4- fluorophenyl) Acetamide；
(R) -2- ((6- ((3R, 4R) -4- amino -3- hydroxy piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((6- ((R) -3- amino-pyrrolidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((6- (3- (amino methyl) pyrrolidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (methylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- (4- Fluorophenyl) acetamide；
2- ((3,5- dicyano -6- (4- (cyclopropylamino) -3- fluorine resources -1- base) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((6- ((S) -3- amino-pyrrolidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((6- ((2- ((R) -3- amino-pyrrolidine -1- base) ethyl) (methyl) amino) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
3,5- dicyano -6- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- (4- fluorophenyl) acetamide；
(S) -2- ((6- ((3S, 4R) -4- amino -3- fluorine resources -1- base) -3,5- dicyano -4- ethylpyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (neopentyl amino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- (4- (trifluoromethyl) phenyl) acetamide；
((3S, 4R) -1- (6- (((R) -2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl Pyridine -2- base) -3- hydroxy piperidine -4- base) t-butyl carbamate；
Rel- (cis-) -1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) -3- fluorine resources -4- base) t-butyl carbamate；
2- ((6- ((2- ((S) -3- amino-pyrrolidine -1- base) ethyl) (methyl) amino) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
((3R, 4S) -1- (6- (((R) -2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl Pyridine -2- base) -3- hydroxy piperidine -4- base) t-butyl carbamate；
Rel- (cis-) -1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) -3- fluorine resources -4- base) t-butyl carbamate；
2- ((3,5- dicyano -6- ((S) -3- (dimethylamino) pyrrolidin-1-yl) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
(S) -2- ((6- ((3R, 4S) -4- amino -3- fluorine resources -1- base) -3,5- dicyano -4- ethylpyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- ((2- hydroxy-2-methyl propyl) amino) pyrrolidin-1-yl) Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
((3R, 4R) -1- (6- (((R) -2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl Pyridine -2- base) -3- hydroxy piperidine -4- base) t-butyl carbamate；
2- ((3,5- dicyano -6- ((S) -3- (dimethylamino) pyrrolidin-1-yl) -4- ethylpyridine -2- base) sulphur Base) -2- (4- fluorophenyl) acetamide；
Rel-2- ((cis- -4- amino -3- fluorine resources -1- base of 6-) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (methylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -6- (4- (dimethylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (ethyl (methyl) amino) piperidin-1-yl) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (neopentyl amino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (methyl (neopentyl) amino) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- (cyclopropylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- ((2- methoxy ethyl) amino) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- ((2,2- bis-fluoro ethyls) amino) piperidin-1-yl) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((R) -2- ((neopentyl amino) methyl) morpholino) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (2- ((dimethylamino) methyl) morpholino) -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -6- (2- ((diethylamino) methyl) morpholino) -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (2- (pyrrolidin-1-yl methyl) morpholino) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
(R) -2- ((6- ((R) -2- (amino methyl) morpholino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((6- (2- (amino methyl) morpholino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- ethyl -6- (2- ((methylamino) methyl) morpholino) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((6- ((R) -2- (amino methyl) morpholino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -6- (3- ((dimethylamino) methyl) piperidin-1-yl) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (3- ((methylamino) methyl) piperidin-1-yl) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((S) -2- ((neopentyl amino) methyl) morpholino) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- ((neopentyl amino) methyl) piperidin-1-yl) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- amino-N- (((2S) -4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- second Yl pyridines-2- base) morpholine -2-yl) methyl)-2- methyl propanamide；
2- ((6- ((S) -3- (amino methyl) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -6- ((R) -2- ((diethylamino) methyl) morpholino) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- amino-N- (((2R) -4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- second Yl pyridines-2- base) morpholine -2-yl) methyl)-2- methyl propanamide；
2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- (3- fluorine pyridine - 2- yl) acetamide；
2- ((6- ((S) -2- (amino methyl) morpholino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- amino-N- (((3S) -1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- second Yl pyridines -2- base) piperidines -3- base) methyl) -2- methyl propanamide；
2- amino-N- (((3S) -1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- second Yl pyridines -2- base) piperidines -3- base) methyl) acetamide；
2- amino-N- (((2R) -4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- second Yl pyridines-2- base) morpholine -2-yl) methyl) acetamide；
2- ((6- ((R) -3- (amino methyl) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- (4- fluorophenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((R) -3- ((neopentyl amino) methyl) piperidin-1-yl) pyridine -2- base) Sulfenyl) -2- (4- fluorophenyl) acetamide；
2- amino-N- (((2S) -4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- second Yl pyridines-2- base) morpholine -2-yl) methyl) acetamide；
N- (((R) -4- (6- (((R) -2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine-2- base) morpholine -2-yl) methyl)-2- hydroxyl acetamide；
(S) -2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (first Base) amino)-N- (2- hydroxyethyl)-N- methylacetamide；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- (methylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((6- (4- amino -4- methyl piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (first Base) amino)-N- ((1- (hydroxymethyl) cyclopropyl) methyl)-N- methylacetamide；
2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyrrole Pyridine -2- base) azetidine -3- base) acetamide；
(2S) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ring PropyIpyridine -2- base) azetidine -3- base) -3- hydroxypropanamide；
2- ((6- ((S) -3- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((R) -3- hydroxyl pyrrolidine -1- base) -2- oxoethyl) (methyl) Amino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
(2R) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ring PropyIpyridine -2- base) azetidine -3- base) -3- hydroxypropanamide；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (first Base) amino)-N- (3- hydroxyl -2,2- dimethyl propyl)-N- methylacetamide；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((S) -3- hydroxyl pyrrolidine -1- base) -2- oxoethyl) (methyl) Amino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((6- (4- amino -4- methyl piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((6- (4- (amino methyl) -4- fluorine resources -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) - 2- phenylacetyl amine hydrochlorate；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine -2- base) (methyl) amino)-N- (2- amino-ethyl) acetamide hydrochloride；
2- ((3,5- dicyano -4- ethyl -6- (methyl (2- oxo -2- (pyrrolidin-1-yl) ethyl) amino) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- (4- hydroxy piperidine -1- base) -2- oxoethyl) (methyl) amino) Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (methyl (2- oxo -2- (piperazine -1- base) ethyl) amino) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (methyl (2- morpholino -2- oxoethyl) amino) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
(R) -2- ((6- ((S) -3- (amino methyl) -3- hydroxyl pyrrolidine -1- base) -3,5- dicyano -4- ethylpyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- (guanidine radicals oxygroup) pyrrolidin-1-yl) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- amino-N- (2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) (methyl) amino) ethyl) -2- methyl propanamide；
2- ((6- ((2- (2- amino ethoxy) ethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
4- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) butyramide；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (first Base) amino)-N- (2- amino-ethyl) acetamide；
2- ((6- ((2- (azetidine -1- base) -2- oxoethyl) (methyl) amino) -3,5- dicyano -4- ethyl Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((6- ((R) -3- (amino methyl) -3- fluoropyrrolidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- (3- hydroxy azetidine -1- base) -2- oxoethyl) (methyl) Amino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (guanidine radicals oxygroup) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((6- (3- aminoazetidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl Acetamide；(single stereoisomers)
2- ((3,5- dicyano -4- ethyl -6- ((R) -3- (methylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((3R, 4S) -3- hydroxyl -4- (hydroxymethyl) pyrrolidin-1-yl) - 2- oxoethyl) (methyl) amino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
(R) -2- ((6- ((S) -3- (amino methyl) -3- fluoropyrrolidine -1- base) -3,5- dicyano -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine -2- base) (methyl) amino)-N- (1,3- dihydroxy propyl- 2- yl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- (oxetanes -3- base amino) piperidin-1-yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine -2- base) (methyl) amino)-N, N- bis- (2- hydroxyethyl) acetamide；
2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyrrole Pyridine -2- base) piperidin-4-yl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- ((2- hydroxyethyl) amino) -4- methyl piperidine -1- base) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- (guanidine radicals oxygroup) ethyl) (methyl) amino) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((6- (4- ((2- amino-ethyl) amino) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((S) -2- (hydroxymethyl) morpholino) -2- oxoethyl) (first Base) amino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((2- ((cis-) -3,4- dihydroxy pyrrolidine -1- base) -2- oxoethyl) (methyl) Amino) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((S) -3- (hydroxymethyl) pyrrolidin-1-yl) -2- oxoethyl) (methyl) amino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((3S, 4S) -3- hydroxyl -4- (hydroxymethyl) pyrrolidin-1-yl) - 2- oxoethyl) (methyl) amino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- (neopentyl amino) piperidin-1-yl) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((R) -3- (hydroxymethyl) pyrrolidin-1-yl) -2- oxoethyl) (methyl) amino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((2- ((3R, 4R) -3,4- dihydroxy pyrrolidine -1- base) -2- oxoethyl) (first Base) amino) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
(R) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl -3- (hydroxymethyl) pyrrolidin-1-yl) pyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
(2S) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ring PropyIpyridine -2- base) piperidin-4-yl) propionamide；
2- ((6- (4- (2- amino ethoxy) piperidin-1-yl) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (4- ((2- hydroxyethyl) amino) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (first Base) amino)-N- (1,3- dihydroxy propyl- 2- yl) acetamide；
2- ((3,5- dicyano -6- ((2- ((3R, 5S) -3,5- dihydroxypiperdine -1- base) -2- oxoethyl) (methyl) Amino) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((2- ((3S, 4S) -3,4- dihydroxy pyrrolidine -1- base) -2- oxoethyl) (first Base) amino) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((2- hydroxyethyl) amino) -4- (hydroxymethyl) piperidin-1-yl) Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((R) -2- (hydroxymethyl) morpholino) -2- oxoethyl) (first Base) amino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (first Base) amino)-N- methoxyl acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((3R, 4R) -3- hydroxyl -4- (hydroxymethyl) pyrrolidin-1-yl) - 2- oxoethyl) (methyl) amino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (first Base) amino)-N- (3- hydroxypropyl)-N- methylacetamide；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (first Base) amino)-N- ((R) -2,3- dihydroxypropyl) acetamide；
2- ((6- (4- ((2- amino -2- oxoethyl) amino) piperidin-1-yl) -3,5- dicyano -4- cyclopropyl pyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (first Base) amino)-N, N- bis- (2- hydroxyethyl) acetamide；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (first Base) amino)-N- (2- hydroxyethyl) acetamide；
2- ((6- ((3- aminopropyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((6- (3- (amino methyl) azetidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (first Base) amino)-N- ((1- (hydroxymethyl) cyclopropyl) methyl) acetamide；
(R) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (2,4 difluorobenzene base) acetamide；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (first Base) amino)-N- (3- (hydroxymethyl) oxetanes -3- base) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (3- (guanidine radicals oxygroup) azetidine -1- base) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (first Base) amino)-N- (3- hydroxypropyl) acetamide；
2- ((3,5- dicyano -6- (4- (2,3- dihydroxypropyl) -1,4- Diazesuberane -1- base) -4- ethyl pyrrole Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (first Base) amino)-N- hydroxyl acetamide；
3- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyrrole Pyridine -2- base) azetidine -3- base) oxetanes -3- formamide；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (2- Fluorophenyl) acetamide；
2- ((3,5- dicyano -6- ((S) -3- (cyclopropylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (first Base) amino)-N- (3- hydroxyl -2,2- dimethyl propyl) acetamide；
N- (2- (4H-1,2,4- triazole-4-yl) ethyl) -2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulphur Base) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) amino) acetamide；
N1- (2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) (methyl) amino) ethyl) oxamides；
2- ((6- (3- (amino methyl) -3- fluorine azetidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
(R) -2- ((3,5- dicyano -4- ethyl -6- ((R) -3- hydroxyl -3- (hydroxymethyl) pyrrolidin-1-yl) pyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((S) -3- ((2,2- bis-fluoro ethyls) amino) piperidin-1-yl) -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((6- ((R) -3- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4-methoxypyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- ((S) -4- hydroxyl isoxazole alkane -2- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
(R) -2- ((3,5- dicyano -4- ethyl -6- ((3- hydroxypropyl) (methyl) amino) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((S) -3- hydroxyl pyrrolidine -1- base) -4-methoxypyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (3- methoxyl group azetidine -1- base) piperidin-1-yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (3- methoxyl group azetidine -1- base) piperidin-1-yl) pyridine -2- Base) sulfenyl) -2- (4- fluorophenyl) acetamide；
(R) -2- ((3,5- dicyano -4- ethyl -6- ((2- hydroxyethyl) (methyl) amino) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
(R) -2- ((6- ((R) -3- (amino methyl) -3- hydroxyl pyrrolidine -1- base) -3,5- dicyano -4- ethylpyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- (cyclobutyl (methyl) amino) piperidin-1-yl) -4- ethylpyridine -2- base) sulphur Base) -2- (4- fluorophenyl) acetamide；With
2- ((3,5- dicyano -4- ethyl -6- (methyl (1- methylpyrrolidin- 3- yl) amino) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, the new formula of the present invention (IVbbr) compound is selected from:
2- { [3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base] sulfanyl } -2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- { [3,5- dicyano -4- cyclopropyl -6- (4- ethyl -1,4- Diazesuberane -1- base) pyridine -2- base] sulphur Alkyl } -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- propyl -1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- { [3,5- dicyano -4- ethyl -6- (4- ethyl -1,4- Diazesuberane -1- base) pyridine -2- base] sulfane Base } -2- phenyl-acetamides；
2- { [3,5- dicyano -4- ethyl -6- (5- oxo -1,4- Diazesuberane -1- base) pyridine -2- base] sulfane Base } -2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- morpholino pyridine -2- base) sulfenyl) -2- (pyridin-4-yl) acetamide；
2- { [3,5- dicyano -4- ethyl -6- (4- methyl -3- oxypiperazin -1- base) pyridine -2- base] sulfanyl } -2- (pyridin-4-yl) acetamide；
2- [(3,5- dicyano -4- ethyl -6- { methyl [2- (morpholine -4- base) ethyl] amino } pyridine -2- base) sulfane Base] -2- phenyl-acetamides；
2- { [3,5- dicyano -4- ethyl -6- (4- propylpiperazine -1- base) pyridine -2- base] sulfanyl } -2- phenylacetyl Amine；
2- ({ 3,5- dicyano -4- ethyl -6- [4- (piperidin-4-yl) piperazine -1- base] pyridine -2- base } sulfanyl) -2- Phenyl-acetamides；
2- ({ 3,5- dicyano -4- cyclopropyl -6- [3- (hydroxymethyl) piperazine -1- base] pyridine -2- base } sulfanyl) -2- Phenyl-acetamides；
2- { [3,5- dicyano -4- cyclopropyl -6- (3- oxypiperazin -1- base) pyridine -2- base] sulfanyl } -2- phenyl second Amide；
2- ({ 3,5- dicyano -4- cyclopropyl -6- [4- (morpholine -4- base) piperidin-1-yl] pyridine -2- base } sulfanyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (2,8- diaza spiro [4.5] decyl- 8- yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (3- (dimethylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (3- methylpiperazine-1-yl) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- cyclopropyl -6- (2- (hydroxymethyl) morpholino) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- cyclopropyl -6- (2,6- thebaine generation) pyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- cyclopropyl -6- (3- (dimethylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((6- (4- (amino methyl) -4- hydroxy piperidine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (3- (methylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((6- (3- amino piperidine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- cyclopropyl -6- (dimethylamino) pyridine -2- base) sulfenyl) -2- (pyridin-4-yl) second Amide；
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (pyridin-4-yl) acetyl Amine；
2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- cyclopropyl -6- (4- (dimethylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- (pyridin-4-yl) second Amide；
2- ((3,5- dicyano -4- cyclopropyl -6- (1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (pyridin-4-yl) acetamide；
2- ((3,5- dicyano -4- cyclopropyl -6- ((R) -3- hydroxy piperidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- (3,5- dicyano -4- cyclopropyl -6- ((S) -3- hydroxy piperidine -1- base) pyridine -2- base sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- cyclopropyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (pyridin-4-yl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- ethyl piperazidine -1- base) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- (1- oxa- -6- azaspiro [3.4] octyl- 6- yl) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((6- (4- (3- aminopropyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- (1,7- diaza spiro [3.5] nonyl- 1- yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (4- (pyrrolidin-1-yl methyl) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
(R) -2- ((3,5- dicyano -6- (1,4- Diazesuberane -1- base) -4- ethylpyridine -2- base) amino) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (2,7- diaza spiro [3.5] nonyl- 7- yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (2,6- diaza spiro [3.4] octyl- 6- yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) propionyl Amine；
2- ((3,5- dicyano -4- ethyl -6- (4- (2- oxo-imidazole alkane -1- base) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- hydroxy piperidine -1- base) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- ethyl -6- (3- oxypiperazin -1- base) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- ((2- methoxy ethyl) (methyl) amino) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (3- methoxyl group azetidine -1- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- morpholino pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- [[6- (azetidine -1- base) -3,5- dicyano -4- ethyl -2- pyridyl group] sulfanyl] -2- phenyl-second Amide；
2- ((3,5- dicyano -4- ethyl -6- (4- oxo-piperidine -1- base) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- (1'- (2- hydroxyethyl)-[4,4'- joins piperidines] -1- base) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((3S, 5R) -3,5- lupetazin -1- base) -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((6- (8- azabicyclo [3.2.1] oct-3-yl (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (2- (hydroxymethyl) morpholino) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
(R) -2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
(R) -2- [(3,5- dicyano -4- ethyl -6- morpholino -2- pyridyl group) sulfanyl] -2- phenvl-acetamide；
2- { [3,5- dicyano -4- ethyl -6- (5- methyl-1,4- Diazesuberane -1- base) pyridine -2- base] sulfane Base } -2- phenyl-acetamides；
2- ({ 3,5- dicyano -4- ethyl -6- [4- (2- methoxy ethyl) -1,4- Diazesuberane -1- base] pyridine - 2- yl } sulfanyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxypropyl) -1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- [4- (6- { [carbamoyl (phenyl) methyl] sulfanyl } -3,5- dicyano -4- ethylpyridine -2- base) -1, 4- Diazesuberane -1- base] methyl acetate；
2- { [3,5- dicyano -4- cyclopropyl -6- (4- methyl -5- oxo -1,4- Diazesuberane -1- base) pyridine - 2- yl] sulfanyl } -2- phenyl-acetamides；
2- { [3,5- dicyano -4- cyclopropyl -6- (5- oxo -1,4- Diazesuberane -1- base) pyridine -2- base] sulphur Alkyl } -2- phenyl-acetamides；
2- { [3,5- dicyano -4- ethyl -6- (4- methyl -5- oxo -1,4- Diazesuberane -1- base) pyridine -2- Base] sulfanyl } -2- phenyl-acetamides；
2- { [3,5- dicyano -6- (1,4- Diazesuberane -1- base) -4- ethylpyridine -2- base] sulfanyl } -2- benzene Yl acetamide；
2- ({ 3,5- dicyano -6- [4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base] -4- (2,2,2- trifluoro Ethyl) pyridine -2- base } sulfanyl) -2- phenyl-acetamides；
(2R) -2- ({ 3,5- dicyano -4- ethyl -6- [4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base] pyrrole Pyridine -2- base } amino) -2- phenyl-acetamides；
2- ({ 6- [(3S) -3- amino-pyrrolidine -1- base] -3,5- dicyano -4- cyclopropyl pyridine -2- base } sulfanyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (2,9- diaza spiro [5.5] hendecane -9- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (hexahydro -1H- pyrrolo- [1,2-a] [1,4] diazacyclo heptantriene -2 (3H)-yl) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (2- methyl -2,9- diaza spiro [5.5] hendecane -9- base) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (2- (Cvclopropvlmethvl) -2,9- diaza spiro [5.5] hendecane -9- base) -4- ethyl Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- (3- (dimethylamino) propyl) piperazine -1- base) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-3-yl) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((6- ([4,4'- joins piperidines] -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((6- (4- (2- amino-ethyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((6- (4- (3- aminopropyl) piperazine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (4- ((4- methylpiperazine-1-yl) methyl) piperidin-1-yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((6- (4- Acetylpiperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- cyclopropyl -6- (dimethylamino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- (4- chlorphenyl) -2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) acetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxyethyl) piperazine -1- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- [(3,5- dicyano -4- cyclopropyl -6- morpholino -2- pyridyl group) sulfanyl] -2- phenvl-acetamide；
2- ((6- (4- benzoyl-piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- ethyl -6- ((5S, 6S) -6- hydroxyl -1- (methyl sulphonyl) -1,8- diaza spiro [4.5] decyl- 8- yl) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4,4- difluoropiperdin -1- base) -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
(R) -2- ((3,5- dicyano -4- ethyl -6- ((R) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- (furans -2- base) -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((6- (4- amino -4- methyl piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) acetamide；
(2S) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- second Yl pyridines -2- base) piperidin-4-yl) propionamide；
2- ((6- (4- (3- amino oxetanes -3- carbonyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
4- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) tetrahydro -2H- pyrans -4- formamide；
2- ((6- (4- (4- amino tetrahydro -2H- pyrans -4- carbonyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base) -4-methoxypyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((6- ((2- amino-ethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((6- ((2- amino -2- oxoethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (3- hydroxy azetidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- (3,5- dicyano -4- ethyl -6- ((2- hydroxyethyl) (methyl) amino) pyridine -2- base sulfenyl) -2- phenyl Acetamide；
2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) -2- methyl propanamide；
2- ((6- (4- (2- amino ethoxy) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
Biphosphate 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) pyrrolidin-3-yl ester；
Biphosphate 2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) (methyl) amino) ethyl ester；
Biphosphate 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) azetidine -3- base ester；
(2S) -2- amino -3 Methylbutanoic acid 2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- Dicyano -4- ethylpyridine -2- base) piperidin-4-yl) oxygroup) ethyl ester；
Biphosphate 2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) oxygroup) ethyl ester；
Biphosphate 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) piperidin-4-yl ester；
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (piperidin-4-yl) acetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- (4- (sulfonyl propyl base) piperazine -1- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (phenyl sulfonyl) piperazine -1- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((R) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- ethyl -6- (2- oxa- -6- azaspiro [3.4] octyl- 6- yl) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
(R) -2- ((3,5- dicyano -4- ethyl -6- (4- ethyl -1,4- Diazesuberane -1- base) pyridine -2- base) Amino) -2- phenyl-acetamides；
(R) -2- ((3,5- dicyano -4- ethyl -6- (4- (3- (pyrrolidin-1-yl) propyl) -1,4- diaza cycloheptyl Alkane -1- base) pyridine -2- base) amino) -2- phenyl-acetamides；
2- (3,5- dicyano -4- cyclopropyl -6- (3- hydroxy piperidine -1- base) pyridine -2- base sulfenyl) -2- phenylacetyl Amine；
2- ((the chloro- 4- ethyl -6- of 3,5- bis- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -6- (1,1- sulfur dioxide morpholino) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- ethyl -6- (methyl (2- (piperazine -1- base) ethyl) amino) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
(R) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((6- ((2- (4- (amino methyl) -4- hydroxy piperidine -1- base) ethyl) (methyl) amino) -3,5- dicyano - 4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((4- cyano -3- (1,4- Diazesuberane -1- base) -6,7- dihydro -5H- cyclopenta [c] pyridine -1- Base) sulfenyl) -2- phenyl-acetamides；
2- ((6- (4- (1H- imidazoles -1- base) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (pyridin-4-yl methyl) piperazine -1- base) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -6- (2- (dimethylamino) ethyoxyl) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine -2- Base) piperidines -3- base) amino) acetic acid；
2- ((3,5- dicyano -4- ethyl -6- (4- (oxazole -2- ylmethyl) piperazine -1- base) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((6- (4- ((1H- pyrroles -2- base) methyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (- 2 (1H)-yl of 3,4- dihydro -2,7- benzodiazine) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (pyrrole Pyridine -3- base) acetamide；
2- ((6- (4- ((1H- pyrroles -3- base) methyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (isoxazole -3- ylmethyl) piperazine -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (oxazole -5- ylmethyl) piperazine -1- base) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (isoxazole -4- ylmethyl) piperazine -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
3- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) oxetanes -3- formamide；
2- ((6- (4- ((1H- pyrazoles -4- base) methyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((6- (4- ((1H- imidazoles -5- base) methyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (1- hydroxy-2-methyl propyl- 2- yl) piperazine -1- base) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((6- (4- ((1H- imidazoles -2- base) methyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (dimethylamino) -4-methoxypyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (dimethylamino) -4- ethoxy pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyoxyl -6- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base) pyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxy-2-methyl propyl) -1,4- Diazesuberane -1- base) Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (thiazole -5- ylmethyl) piperazine -1- base) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- (4- fluorophenyl) acetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- (4- (isothiazole -4- ylmethyl) piperazine -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (4- fluorophenyl) acetyl Amine；
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (5- fluorine pyridine -2- base) Acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (furans -3- ylmethyl) piperazine -1- base) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- morpholinoethyl) sulfenyl) pyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -6- (4- methyl-1,4- Diazesuberane -1- base) -4- (methylsulfany) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((the chloro- 4- ethyl -6- of 3,5- bis- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (hexahydropyrrolo simultaneously [3,4-b] [1,4] oxazines -6 (2H)-yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (5- picoline -2- base) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (6- fluorine pyridine -2- base) acetamide；
2- ((3,5- dicyano -6- (4- (dimethylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- (4- fluorophenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (4- picoline -2- base) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (3-Methoxy Pyridine -2- base) acetamide；
2- ((3,5- dicyano -6- (4- (dimethylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- (2,4 difluorobenzene base) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- (5- fluorine pyridine -2- base) acetamide；
2- ((3,5- dicyano -4- ethyoxyl -6- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base) pyridine - 2- yl) sulfenyl) propionamide；
2- ((3,5- dicyano -6- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base) -4- propoxyl group pyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (4-methoxypyridine -2- base) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (2- methyl -2,8- diaza spiro [4.5] decyl- 8- yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- (dimethylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- (3,4- difluorophenyl) acetamide；
1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperazine Pyridine -4- formamide；
2- ((3,5- dicyano -6- ((2- (dimethylamino) ethyl) sulfenyl) -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -6- ((3S, 4R) -3,4- dihydroxy pyrrolidine -1- base) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (3- fluorine pyridine -2- base) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (5- methoxypyridine -2- base) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (1- hydroxy-2-methyl propyl- 2- yl) piperazine -1- base) pyridine -2- base) Sulfenyl) -2- (4- fluorophenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (3- (trifluoromethyl) phenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxyl-oxethyl) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (2- fluorine pyridin-3-yl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (6- fluorine pyridin-3-yl) acetamide；
3- ((6- (2- amino -2- oxo -1- phenylethyl sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (first Base) amino) propionamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (oxetanes -3- base oxygroup) piperidin-1-yl) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- ((2,2- bis-fluoro ethyls) amino) -4- methyl piperidine -1- base) -4- ethylpyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (4- (trifluoromethyl) phenyl) acetamide；
2- ((6- (4- aminopiperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((6- ((2- amino -2- oxoethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- (pyrrolo- [3,4-c] pyrazoles -5 (1H, 4H, 6H)-yl) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (5- methoxypyridine - 2- yl) acetamide；
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (5- picoline -2- Base) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (2- fluorine pyridin-4-yl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- hydroxyl -4- (hydroxymethyl) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (2- oxo -3- oxa- -1,8- diaza spiro [4.5] decyl- 8- yl) pyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((6- (4- amino -4- (hydroxymethyl) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((6- (4- (amino methyl) -4- hydroxy piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- (3- benzoylphenyl) -2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxyethyl) -1,4- diaza Cycloheptane -1- base) pyridine -2- base) sulfenyl) acetamide；
2- (4- benzoylphenyl) -2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxyethyl) -1,4- diaza Cycloheptane -1- base) pyridine -2- base) sulfenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (2- picoline -4- base) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (3- (pyrrolidin-1-yl) phenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (3- fluorine pyridin-4-yl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (2,5- difluoro pyridine -4- base) acetamide；
2- ((3,5- dicyano -6- (4- (2,5- dioxoimidazolidin -1- base) piperidin-1-yl) -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
4- amino -1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) piperidines -4- formamide；
2- ((3,5- dicyano -6- (4- (2,5- dioxo pyrrolidin -1- base) piperidin-1-yl) -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides (isomers 1)；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides (isomers 2)；
2- ((3,5- dicyano -4- ethyl -6- (2- oxo -1- oxa- -3,8- diaza spiro [4.5] decyl- 8- yl) pyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) -4- Hydroxy piperidine -4- formamide；
Carbamic acid 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) azetidine -3- base ester；
2- ((3,5- dicyano -6- (4- (2,4- dioxo oxazolidine -3- base) piperidin-1-yl) -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
3- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (first Base) amino) -2- hydroxy-2-methyl propionamide；
2- ((3,5- dicyano -4- ethyl -6- (3- (hydroxymethyl) azetidine -1- base) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- (3,5- dicyano -4- ethyl -6- (piperazine -1- base) pyridine -2- base sulfenyl) -2- (thiene-3-yl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (5- picoline -3- base) acetamide；
2- ((6- (4- (3- amino -2- oxo-pyrrolidine -1- base) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
(2S) -2- amino -3 Methylbutanoic acid 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyan Base -4- ethylpyridine -2- base) piperidin-4-yl ester；
(2S) -2- amino -3 Methylbutanoic acid 2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyan Base -4- ethylpyridine -2- base) (methyl) amino) ethyl ester；
2,2'- ((3,5- dicyano -4- ethylpyridine -2,6- diyl) bis- (sulfane diyls)) bis- (2- phenyl-acetamides)；
(2S) -2- amino -3 Methylbutanoic acid (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyan Base-4-ethylpyridine-2- base) azetidine-3- base) methyl ester；
2- ((6- (3- aminoazetidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- ethyl -6- picoline -2- base) sulfenyl) -2- phenyl-acetamides；
N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) Piperidin-4-yl) -2- hydroxyl acetamide；
N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) Azetidine -3- base) -2- hydroxyl acetamide；
2- ((3- cyano -4- ethyl -5- methyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (5- methyl -2,5- diazabicyclo [2.2.1] hept- 2- yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (2- (pyrrolidin-1-yl) ethyl) piperazine -1- base) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides -2-d；
(R) -2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides - 2-d；
2- ((6- (4- (4- benzoyl bromide) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- cyano piperidine -1- base) -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
(S) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((6- (4- amino -4- methyl piperidine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (pyrrole Pyridine -2- base) acetamide；
2- ((3,5- bis- chloro- 4- ethyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
(1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperazine Pyridine -4- base) t-butyl carbamate；
2- ((6- (3- (2- amino -2- oxoethyl) azetidine -1- base) -3,5- dicyano -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
(2R) -2- amino -3 Methylbutanoic acid 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyan Base -4- ethylpyridine -2- base) azetidine -3- base ester；
2- ((3,5- dicyano -4- ethyl -6- (methyl ((5- oxo -4,5- dihydro -1H-1,2,4- triazole -3- base) first Base) amino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((6- (((4H-1,2,4- triazole -3- base) methyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyoxyl -6- picoline -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4,6- parvoline -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((6- ((2- (4H-1,2,4- triazole-4-yl) ethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((6- (((1H- pyrazole-3-yl) methyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (6,7- dihydro -1H- [1,2,3] triazol [4,5-c] pyridine -5 (4H)-yl) -4- second Yl pyridines -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((6- (((1H- imidazoles -2- base) methyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((6- (((1H- imidazoles -5- base) methyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
(2R) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- second Yl pyridines -2- base) piperidin-4-yl) propionamide；
4- (2- amino -1- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine - 2- yl) sulfenyl) -2- oxoethyl) benzamide；
2- ((3,5- dicyano -4- cyclopropyl -6- (3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- ethyl -6- (3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
(2R) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ring PropyIpyridine -2- base) piperidin-4-yl) propionamide；
2- ((6- ((2- amino-ethyl) (methyl) amino) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyrrole Pyridine -2- base) piperidin-4-yl) -2- methyl propanamide；
4- (2- amino -1- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- oxo Ethyl) benzamide；
2- (6- (4- amino piperidine -1- base) -3- cyano -4- ethyl -5- picoline -2- base sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (4- (N- Methylsulfamoyl) phenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (the fluoro- 1,4- Diazesuberane -1- base of 6-) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((6- (4- amino -3,3- difluoropiperdin -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
(1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) -3, 3- difluoropiperdin -4- base) t-butyl carbamate；
2- ((3,5- dicyano -4- cyclopropyl -6- ((2- hydroxyethyl) (methyl) amino) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (3- hydroxy azetidine -1- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) pyrroles Alkane -3- formamide；
2- ((6- ((3- aminopropyl) (methyl) amino) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- ((2- (3- hydroxy azetidine -1- base) -2- oxoethyl) (first Base) amino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((6- (4- ((2- amino -2- oxoethyl) amino) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((6- ((2- amino -2- oxoethyl) (methyl) amino) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
Carbamic acid 2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyrrole Pyridine -2- base) (methyl) amino) ethyl ester；
(2R) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- second Yl pyridines -2- base) piperidin-4-yl) -3- hydroxypropanamide；
(2S) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- second Yl pyridines -2- base) piperidin-4-yl) -3- hydroxypropanamide；
2- (4- (2- amino -2- oxoethyl) phenyl) -2- (3,5- dicyano -4- ethyl -6- (4- methyl-1,4- phenodiazine Trioxepane -1- base) pyridine -2- base sulfenyl) acetamide；
2- (4- (2- amino -2- oxoethyl) phenyl) -2- (3,5- dicyano -6- (dimethylamino) -4- ethyl pyrrole Pyridine -2- base sulfenyl) acetamide；
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (4- (N- methyl ammonia sulphur Acyl group) phenyl) acetamide；
2- ((3,5- dicyano -6- (dimethylamino-d6) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
(R) -2- ((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
(R) -2- ((3,5- dicyano -6- (4- (dimethylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- (3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base sulfenyl) -2- (3- (2- (dimethylamino Base) ethyoxyl) phenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (neopentyl amino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- (4- fluorophenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (the fluoro- 4- of 3- (neopentyl amino) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- (4- (fluoroform Base) phenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
(R) -2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((6- ((2- amino -2- oxoethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；(single enantiomer)
Biphosphate (3S) -1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl Pyridine -2- base) pyrrolidin-3-yl ester；
Biphosphate (3R) -1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl Pyridine -2- base) pyrrolidin-3-yl ester；
Biphosphate (S) -1- (6- (((S) -2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- second Yl pyridines -2- base) pyrrolidin-3-yl ester；
Biphosphate (S) -1- (6- (((R) -2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- second Yl pyridines -2- base) pyrrolidin-3-yl ester；
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (3- (solutions of dimethyl phosphoryl Base) phenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (3- (solutions of dimethyl phosphoryl base) phenyl) acetamide；
Biphosphate (R) -2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl Pyridine -2- base) (methyl) amino) ethyl ester；
(R) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (4- methoxyphenyl) acetamide；
(R) -2- (4- chlorphenyl) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine - 2- yl) sulfenyl) acetamide；
(R) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (4- fluorophenyl) acetamide；
Biphosphate (S) -1- (6- (((R) -2- amino -1- (4- fluorophenyl) -2- oxoethyl) sulfenyl) -3,5- dicyan Base -4- ethylpyridine -2- base) pyrrolidin-3-yl ester；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (4- Fluorophenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (2, 6- difluorophenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (2, 3- difluorophenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (2, 4- difluorophenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- ((S) -2- (hydroxymethyl) pyrrolidin-1-yl) piperidin-1-yl) pyrrole Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((2- hydroxyethyl) (methyl) amino) piperidin-1-yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((2- hydroxy-2-methyl propyl) (methyl) amino) piperidin-1-yl) Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-1-yl methyl) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((2- methoxyl group -2- methyl-propyl) amino) piperidin-1-yl) pyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((2- hydroxy-2-methyl propyl) amino) piperidin-1-yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- (Cyclobutylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (((3- methy oxetane -3- base) methyl) amino) piperidines -1- Base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((R) -2- methylpyrrolidin- 1- yl) piperidin-1-yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- ((2R, 5S) -2,5- dimethyl pyrrolidine -1- base) piperidin-1-yl) -4- ethyl Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((S) -2- methylpyrrolidin- 1- yl) piperidin-1-yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- (cyclobutyl (methyl) amino) piperidin-1-yl) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- (6- (4- (benzylamino) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- ethyl -6- (4- (((6- methoxypyridine -2- base) methyl) amino) piperidin-1-yl) Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((S) -3- fluoropyrrolidine -1- base) piperidin-1-yl) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (methyl (2- ((R) -2- methylpyrrolidin- 1- yl) ethyl) amino) pyrrole Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((R) -3- fluoropyrrolidine -1- base) piperidin-1-yl) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- ((2S, 5S) -2,5- dimethyl pyrrolidine -1- base) piperidin-1-yl) -4- ethyl Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (methyl (2- ((S) -2- methylpyrrolidin- 1- yl) ethyl) amino) pyrrole Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((R) -2- (hydroxymethyl) pyrrolidin-1-yl) piperidin-1-yl) pyrrole Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- (dimethylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- (4- fluorophenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (((1- methyl-cyclobutyl) methyl) amino) piperidin-1-yl) pyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (((6- methoxypyridine -3- base) methyl) amino) piperidin-1-yl) Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- (3,5- dicyano -4- ethyl -6- ((2- (ethylamino) ethyl) (methyl) amino) pyridine -2- base sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((4- methylpiperazine-1-yl) methyl) piperidin-1-yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (methyl (2- (methylamino) ethyl) amino) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- ((2R, 5R) -2,5- dimethyl pyrrolidine -1- base) piperidin-1-yl) -4- ethyl Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (((1- methylcyclopropyl groups) methyl) amino) piperidin-1-yl) pyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((4- luorobenzyl) amino) piperidin-1-yl) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((S) -2- (hydroxymethyl) pyrrolidin-1-yl) ethyl) (methyl) Amino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- (3,5- dicyano -6- ((2- ((2S, 5R) -2,5- dimethyl pyrrolidine -1- base) ethyl) (methyl) amino) - 4- ethylpyridine -2- base sulfenyl) -2- phenyl-acetamides；
2- ((6- ((2- (azepan -1- base) ethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (methyl (2- (piperidin-1-yl) ethyl) amino) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((R) -2- (hydroxymethyl) pyrrolidin-1-yl) ethyl) (methyl) Amino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- (3,5- dicyano -4- ethyl -6- ((2- (ethyl (methyl) amino) ethyl) (methyl) amino) pyridine -2- base Sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((2- ((2R, 5R) -2,5- dimethyl pyrrolidine -1- base) ethyl) (methyl) amino) - 4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- (3,5- dicyano -4- ethyl -6- ((2- ((S) -3- hydroxyl pyrrolidine -1- base) ethyl) (methyl) amino) pyrrole Pyridine -2- base sulfenyl) -2- phenyl-acetamides；
2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) Piperidin-4-yl) amino) -2 Methylpropionic acid methyl esters；
2- ((3,5- dicyano -4- ethyl -6- (methyl (2- (neopentyl amino) ethyl) amino) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- (3,5- dicyano -4- ethyl -6- (methyl (2- (1- methylcyclopropyl groups amino) ethyl) amino) pyridine -2- base Sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((2- ((2S, 5S) -2,5- dimethyl pyrrolidine -1- base) ethyl) (methyl) amino) - 4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((2- methoxy ethyl) amino) ethyl) (methyl) amino) pyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((2- methoxyl group -2- methyl-propyl) (methyl) amino) piperidines -1- Base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((2- (dimethylamino) ethyl) (methyl) amino) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- (3,5- dicyano -4- ethyl -6- ((2- ((R) -3- hydroxyl pyrrolidine -1- base) ethyl) (methyl) amino) pyrrole Pyridine -2- base sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((2- fluoro ethyl) amino) ethyl) (methyl) amino) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- (3,3- difluoropyrrolidin -1- base) piperidin-1-yl) -4- ethylpyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) Piperidin-4-yl) amino) acetic acid；
2- ((6- ((3- Aminocyclobutyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
(R) -2- (3,5- dicyano -4- ethyl -6- (methyl ((R)-tetrahydrofuran -3- base) amino) pyridine -2- base sulphur Base) -2- phenyl-acetamides；
(S) -2- (3,5- dicyano -4- ethyl -6- (methyl ((R)-tetrahydrofuran -3- base) amino) pyridine -2- base sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- morpholino piperidin-1-yl) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxyethyl) -3- oxypiperazin -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- (4- fluorophenyl) acetamide；
(R) -2- ((6- ((3S, 4R) -4- amino -3- fluorine resources -1- base) -3,5- dicyano -4- ethylpyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (3- fluoro- 4- (methylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
Rel-2- ((6- (trans-) -4- amino -3- fluorine resources -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
(R) -2- ((6- ((3R, 4S) -4- amino -3- fluorine resources -1- base) -3,5- dicyano -4- ethylpyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (the fluoro- 4- of 3- ((2- methoxy ethyl) amino) piperidin-1-yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (methyl (2- (pyrrolidin-1-yl) ethyl) amino) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (3- ((dimethylamino) methyl) pyrrolidin-1-yl) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((2- hydroxy-2-methyl propyl) amino) piperidin-1-yl) pyridine -2- Base) sulfenyl) -2- (4- fluorophenyl) acetamide；
(R) -2- ((6- ((3S, 4R) -4- amino -3- hydroxy piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((2- (diethylamino) ethyl) (methyl) amino) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((2- ((R) -3- (dimethylamino) pyrrolidin-1-yl) ethyl) (methyl) amino) - 4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((2- ((S) -3- (dimethylamino) pyrrolidin-1-yl) ethyl) (methyl) amino) - 4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
(R) -2- ((6- ((3R, 4R) -4- amino -3- fluorine resources -1- base) -3,5- dicyano -4- ethylpyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
(R) -2- ((6- ((3S, 4S) -4- amino -3- fluorine resources -1- base) -3,5- dicyano -4- ethylpyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (3- (methylamino) pyrrolidin-1-yl) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- (4- fluorophenyl) Acetamide；
(R) -2- ((6- ((3R, 4R) -4- amino -3- hydroxy piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((6- ((R) -3- amino-pyrrolidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((6- (3- (amino methyl) pyrrolidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (methylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- (4- Fluorophenyl) acetamide；
2- ((3,5- dicyano -6- (4- (cyclopropylamino) -3- fluorine resources -1- base) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((6- ((S) -3- amino-pyrrolidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((6- ((2- ((R) -3- amino-pyrrolidine -1- base) ethyl) (methyl) amino) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
3,5- dicyano -6- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- (4- fluorophenyl) acetamide；
(S) -2- ((6- ((3S, 4R) -4- amino -3- fluorine resources -1- base) -3,5- dicyano -4- ethylpyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (neopentyl amino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- (4- (trifluoromethyl) phenyl) acetamide；
((3S, 4R) -1- (6- (((R) -2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl Pyridine -2- base) -3- hydroxy piperidine -4- base) t-butyl carbamate；
Rel- (cis-) -1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) -3- fluorine resources -4- base) t-butyl carbamate；
2- ((6- ((2- ((S) -3- amino-pyrrolidine -1- base) ethyl) (methyl) amino) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
((3R, 4S) -1- (6- (((R) -2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl Pyridine -2- base) -3- hydroxy piperidine -4- base) t-butyl carbamate；
Rel- (cis-) -1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) -3- fluorine resources -4- base) t-butyl carbamate；
2- ((3,5- dicyano -6- ((S) -3- (dimethylamino) pyrrolidin-1-yl) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
(S) -2- ((6- ((3R, 4S) -4- amino -3- fluorine resources -1- base) -3,5- dicyano -4- ethylpyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- ((2- hydroxy-2-methyl propyl) amino) pyrrolidin-1-yl) Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
((3R, 4R) -1- (6- (((R) -2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl Pyridine -2- base) -3- hydroxy piperidine -4- base) t-butyl carbamate；
2- ((3,5- dicyano -6- ((S) -3- (dimethylamino) pyrrolidin-1-yl) -4- ethylpyridine -2- base) sulphur Base) -2- (4- fluorophenyl) acetamide；
Rel-2- ((cis- -4- amino -3- fluorine resources -1- base of 6-) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (methylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -6- (4- (dimethylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (ethyl (methyl) amino) piperidin-1-yl) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (neopentyl amino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (methyl (neopentyl) amino) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- (cyclopropylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- ((2- methoxy ethyl) amino) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- ((2,2- bis-fluoro ethyls) amino) piperidin-1-yl) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((R) -2- ((neopentyl amino) methyl) morpholino) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (2- ((dimethylamino) methyl) morpholino) -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -6- (2- ((diethylamino) methyl) morpholino) -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (2- (pyrrolidin-1-yl methyl) morpholino) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
(R) -2- ((6- ((R) -2- (amino methyl) morpholino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((6- (2- (amino methyl) morpholino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- ethyl -6- (2- ((methylamino) methyl) morpholino) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((6- ((R) -2- (amino methyl) morpholino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -6- (3- ((dimethylamino) methyl) piperidin-1-yl) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (3- ((methylamino) methyl) piperidin-1-yl) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((S) -2- ((neopentyl amino) methyl) morpholino) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- ((neopentyl amino) methyl) piperidin-1-yl) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- amino-N- (((2S) -4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- second Yl pyridines-2- base) morpholine -2-yl) methyl)-2- methyl propanamide；
2- ((6- ((S) -3- (amino methyl) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -6- ((R) -2- ((diethylamino) methyl) morpholino) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- amino-N- (((2R) -4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- second Yl pyridines-2- base) morpholine -2-yl) methyl)-2- methyl propanamide；
2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- (3- fluorine pyridine - 2- yl) acetamide；
2- ((6- ((S) -2- (amino methyl) morpholino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- amino-N- (((3S) -1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- second Yl pyridines -2- base) piperidines -3- base) methyl) -2- methyl propanamide；
2- amino-N- (((3S) -1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- second Yl pyridines -2- base) piperidines -3- base) methyl) acetamide；
2- amino-N- (((2R) -4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- second Yl pyridines-2- base) morpholine -2-yl) methyl) acetamide；
2- ((6- ((R) -3- (amino methyl) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- (4- fluorophenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((R) -3- ((neopentyl amino) methyl) piperidin-1-yl) pyridine -2- base) Sulfenyl) -2- (4- fluorophenyl) acetamide；
2- amino-N- (((2S) -4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- second Yl pyridines-2- base) morpholine -2-yl) methyl) acetamide；
N- (((R) -4- (6- (((R) -2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine-2- base) morpholine -2-yl) methyl)-2- hydroxyl acetamide；
(S) -2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (first Base) amino)-N- (2- hydroxyethyl)-N- methylacetamide；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- (methylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((6- (4- amino -4- methyl piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (first Base) amino)-N- ((1- (hydroxymethyl) cyclopropyl) methyl)-N- methylacetamide；
2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyrrole Pyridine -2- base) azetidine -3- base) acetamide；
(2S) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ring PropyIpyridine -2- base) azetidine -3- base) -3- hydroxypropanamide；
2- ((6- ((S) -3- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((R) -3- hydroxyl pyrrolidine -1- base) -2- oxoethyl) (methyl) Amino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
(2R) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ring PropyIpyridine -2- base) azetidine -3- base) -3- hydroxypropanamide；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (first Base) amino)-N- (3- hydroxyl -2,2- dimethyl propyl)-N- methylacetamide；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((S) -3- hydroxyl pyrrolidine -1- base) -2- oxoethyl) (methyl) Amino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((6- (4- amino -4- methyl piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((6- (4- (amino methyl) -4- fluorine resources -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) - 2- phenylacetyl amine hydrochlorate；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine -2- base) (methyl) amino)-N- (2- amino-ethyl) acetamide hydrochloride；
2- ((3,5- dicyano -4- ethyl -6- (methyl (2- oxo -2- (pyrrolidin-1-yl) ethyl) amino) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- (4- hydroxy piperidine -1- base) -2- oxoethyl) (methyl) amino) Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (methyl (2- oxo -2- (piperazine -1- base) ethyl) amino) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (methyl (2- morpholino -2- oxoethyl) amino) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
(R) -2- ((6- ((S) -3- (amino methyl) -3- hydroxyl pyrrolidine -1- base) -3,5- dicyano -4- ethylpyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- (guanidine radicals oxygroup) pyrrolidin-1-yl) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- amino-N- (2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) (methyl) amino) ethyl) -2- methyl propanamide；
2- ((6- ((2- (2- amino ethoxy) ethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
4- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) butyramide；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (first Base) amino)-N- (2- amino-ethyl) acetamide；
2- ((6- ((2- (azetidine -1- base) -2- oxoethyl) (methyl) amino) -3,5- dicyano -4- ethyl Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((6- ((R) -3- (amino methyl) -3- fluoropyrrolidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- (3- hydroxy azetidine -1- base) -2- oxoethyl) (methyl) Amino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (guanidine radicals oxygroup) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((6- (3- aminoazetidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl Acetamide；(single stereoisomers)
2- ((3,5- dicyano -4- ethyl -6- ((R) -3- (methylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((3R, 4S) -3- hydroxyl -4- (hydroxymethyl) pyrrolidin-1-yl) - 2- oxoethyl) (methyl) amino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
(R) -2- ((6- ((S) -3- (amino methyl) -3- fluoropyrrolidine -1- base) -3,5- dicyano -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine -2- base) (methyl) amino)-N- (1,3- dihydroxy propyl- 2- yl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- (oxetanes -3- base amino) piperidin-1-yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine -2- base) (methyl) amino)-N, N- bis- (2- hydroxyethyl) acetamide；
2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyrrole Pyridine -2- base) piperidin-4-yl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- ((2- hydroxyethyl) amino) -4- methyl piperidine -1- base) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- (guanidine radicals oxygroup) ethyl) (methyl) amino) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((6- (4- ((2- amino-ethyl) amino) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((S) -2- (hydroxymethyl) morpholino) -2- oxoethyl) (first Base) amino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((2- ((cis-) -3,4- dihydroxy pyrrolidine -1- base) -2- oxoethyl) (methyl) Amino) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((S) -3- (hydroxymethyl) pyrrolidin-1-yl) -2- oxoethyl) (methyl) amino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((3S, 4S) -3- hydroxyl -4- (hydroxymethyl) pyrrolidin-1-yl) - 2- oxoethyl) (methyl) amino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- (neopentyl amino) piperidin-1-yl) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((R) -3- (hydroxymethyl) pyrrolidin-1-yl) -2- oxoethyl) (methyl) amino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((2- ((3R, 4R) -3,4- dihydroxy pyrrolidine -1- base) -2- oxoethyl) (first Base) amino) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
(R) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl -3- (hydroxymethyl) pyrrolidin-1-yl) pyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
(2S) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ring PropyIpyridine -2- base) piperidin-4-yl) propionamide；
2- ((6- (4- (2- amino ethoxy) piperidin-1-yl) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (4- ((2- hydroxyethyl) amino) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (first Base) amino)-N- (1,3- dihydroxy propyl- 2- yl) acetamide；
2- ((3,5- dicyano -6- ((2- ((3R, 5S) -3,5- dihydroxypiperdine -1- base) -2- oxoethyl) (methyl) Amino) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((2- ((3S, 4S) -3,4- dihydroxy pyrrolidine -1- base) -2- oxoethyl) (first Base) amino) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((2- hydroxyethyl) amino) -4- (hydroxymethyl) piperidin-1-yl) Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((R) -2- (hydroxymethyl) morpholino) -2- oxoethyl) (first Base) amino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (first Base) amino)-N- methoxyl acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((3R, 4R) -3- hydroxyl -4- (hydroxymethyl) pyrrolidin-1-yl) - 2- oxoethyl) (methyl) amino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (first Base) amino)-N- (3- hydroxypropyl)-N- methylacetamide；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (first Base) amino)-N- ((R) -2,3- dihydroxypropyl) acetamide；
2- ((6- (4- ((2- amino -2- oxoethyl) amino) piperidin-1-yl) -3,5- dicyano -4- cyclopropyl pyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (first Base) amino)-N, N- bis- (2- hydroxyethyl) acetamide；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (first Base) amino)-N- (2- hydroxyethyl) acetamide；
2- ((6- ((3- aminopropyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((6- (3- (amino methyl) azetidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (first Base) amino)-N- ((1- (hydroxymethyl) cyclopropyl) methyl) acetamide；
(R) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (2,4 difluorobenzene base) acetamide；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (first Base) amino)-N- (3- (hydroxymethyl) oxetanes -3- base) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (3- (guanidine radicals oxygroup) azetidine -1- base) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (first Base) amino)-N- (3- hydroxypropyl) acetamide；
2- ((3,5- dicyano -6- (4- (2,3- dihydroxypropyl) -1,4- Diazesuberane -1- base) -4- ethyl pyrrole Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (first Base) amino)-N- hydroxyl acetamide；
3- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyrrole Pyridine -2- base) azetidine -3- base) oxetanes -3- formamide；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (2- Fluorophenyl) acetamide；
2- ((3,5- dicyano -6- ((S) -3- (cyclopropylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (first Base) amino)-N- (3- hydroxyl -2,2- dimethyl propyl) acetamide；
N- (2- (4H-1,2,4- triazole-4-yl) ethyl) -2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulphur Base) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) amino) acetamide；
N1- (2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) (methyl) amino) ethyl) oxamides；
2- ((6- (3- (amino methyl) -3- fluorine azetidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
(R) -2- ((3,5- dicyano -4- ethyl -6- ((R) -3- hydroxyl -3- (hydroxymethyl) pyrrolidin-1-yl) pyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((S) -3- ((2,2- bis-fluoro ethyls) amino) piperidin-1-yl) -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((6- ((R) -3- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4-methoxypyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- ((S) -4- hydroxyl isoxazole alkane -2- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
(R) -2- ((3,5- dicyano -4- ethyl -6- ((3- hydroxypropyl) (methyl) amino) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((S) -3- hydroxyl pyrrolidine -1- base) -4-methoxypyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (3- methoxyl group azetidine -1- base) piperidin-1-yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；With
2- ((3,5- dicyano -4- ethyl -6- (4- (3- methoxyl group azetidine -1- base) piperidin-1-yl) pyridine -2- Base) sulfenyl) -2- (4- fluorophenyl) acetamide；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, the new formula of the present invention (IVbbr) compound is selected from:
2- { [3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base] sulfanyl } -2- phenyl-acetamides；
2- ((6- ((2- amino -2- oxoethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
(R) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- (4- fluorophenyl) Acetamide；
2- ((3,5- dicyano -6- (4- (cyclobutyl (methyl) amino) piperidin-1-yl) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (the fluoro- 4- of 3- (neopentyl amino) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
(R) -2- ((3,5- dicyano -4- ethyl -6- ((2- hydroxyethyl) (methyl) amino) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- (cyclobutyl (methyl) amino) piperidin-1-yl) -4- ethylpyridine -2- base) sulphur Base) -2- (4- fluorophenyl) acetamide；With
2- ((3,5- dicyano -4- ethyl -6- (methyl (1- methylpyrrolidin- 3- yl) amino) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, the new formula of the present invention (IVbbr) compound is selected from:
(R) -2- ((3,5- dicyano -4- ethyl -6- ((2- hydroxyethyl) (methyl) amino) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- (cyclobutyl (methyl) amino) piperidin-1-yl) -4- ethylpyridine -2- base) sulphur Base) -2- (4- fluorophenyl) acetamide；With
2- ((3,5- dicyano -4- ethyl -6- (methyl (1- methylpyrrolidin- 3- yl) amino) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, the new formula of the present invention (Vbbr) compound is selected from:
2- ((3,5- dicyano -4- cyclopropyl -6- (1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- { [3,5- dicyano -4- cyclopropyl -6- (4- ethyl -1,4- Diazesuberane -1- base) pyridine -2- base] sulphur Alkyl } -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- propyl -1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- { [3,5- dicyano -4- ethyl -6- (4- ethyl -1,4- Diazesuberane -1- base) pyridine -2- base] sulfane Base } -2- phenyl-acetamides；
2- { [3,5- dicyano -4- ethyl -6- (5- oxo -1,4- Diazesuberane -1- base) pyridine -2- base] sulfane Base } -2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- morpholino pyridine -2- base) sulfenyl) -2- (pyridin-4-yl) acetamide；
2- { [3,5- dicyano -4- ethyl -6- (4- methyl -3- oxypiperazin -1- base) pyridine -2- base] sulfanyl } -2- (pyridin-4-yl) acetamide；
2- [(3,5- dicyano -4- ethyl -6- { methyl [2- (morpholine -4- base) ethyl] amino } pyridine -2- base) sulfane Base] -2- phenyl-acetamides；
2- { [3,5- dicyano -4- ethyl -6- (4- propylpiperazine -1- base) pyridine -2- base] sulfanyl } -2- phenylacetyl Amine；
2- ({ 3,5- dicyano -4- ethyl -6- [4- (piperidin-4-yl) piperazine -1- base] pyridine -2- base } sulfanyl) -2- Phenyl-acetamides；
2- ({ 3,5- dicyano -4- cyclopropyl -6- [3- (hydroxymethyl) piperazine -1- base] pyridine -2- base } sulfanyl) -2- Phenyl-acetamides；
2- { [3,5- dicyano -4- cyclopropyl -6- (3- oxypiperazin -1- base) pyridine -2- base] sulfanyl } -2- phenyl second Amide；
2- ({ 3,5- dicyano -4- cyclopropyl -6- [4- (morpholine -4- base) piperidin-1-yl] pyridine -2- base } sulfanyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (2,8- diaza spiro [4.5] decyl- 8- yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (3- (dimethylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (3- methylpiperazine-1-yl) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- cyclopropyl -6- (2- (hydroxymethyl) morpholino) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- cyclopropyl -6- (2,6- thebaine generation) pyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- cyclopropyl -6- (3- (dimethylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((6- (4- (amino methyl) -4- hydroxy piperidine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (3- (methylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((6- (3- amino piperidine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- cyclopropyl -6- (4- (dimethylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- (pyridin-4-yl) second Amide；
2- ((3,5- dicyano -4- cyclopropyl -6- (1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (pyridin-4-yl) acetamide；
2- ((3,5- dicyano -4- cyclopropyl -6- ((R) -3- hydroxy piperidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- (3,5- dicyano -4- cyclopropyl -6- ((S) -3- hydroxy piperidine -1- base) pyridine -2- base sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- cyclopropyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (pyridin-4-yl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- ethyl piperazidine -1- base) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- (1- oxa- -6- azaspiro [3.4] octyl- 6- yl) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((6- (4- (3- aminopropyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- (1,7- diaza spiro [3.5] nonyl- 1- yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (4- (pyrrolidin-1-yl methyl) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
(R) -2- ((3,5- dicyano -6- (1,4- Diazesuberane -1- base) -4- ethylpyridine -2- base) amino) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (2,7- diaza spiro [3.5] nonyl- 7- yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (2,6- diaza spiro [3.4] octyl- 6- yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) propionyl Amine；
2- ((3,5- dicyano -4- ethyl -6- (4- (2- oxo-imidazole alkane -1- base) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- hydroxy piperidine -1- base) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- ethyl -6- (3- oxypiperazin -1- base) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- ((2- methoxy ethyl) (methyl) amino) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (3- methoxyl group azetidine -1- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- morpholino pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- [[6- (azetidine -1- base) -3,5- dicyano -4- ethyl -2- pyridyl group] sulfanyl] -2- phenyl-second Amide；
2- ((3,5- dicyano -4- ethyl -6- (4- oxo-piperidine -1- base) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- (1'- (2- hydroxyethyl)-[4,4'- joins piperidines] -1- base) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((3S, 5R) -3,5- lupetazin -1- base) -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((6- (8- azabicyclo [3.2.1] oct-3-yl (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (2- (hydroxymethyl) morpholino) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
(R) -2- [(3,5- dicyano -4- ethyl -6- morpholino -2- pyridyl group) sulfanyl] -2- phenvl-acetamide；
N- (4- ((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- base sulfenyl) first Base) benzyl) acetamide trifluoroacetate；
2- { [3,5- dicyano -4- ethyl -6- (5- methyl-1,4- Diazesuberane -1- base) pyridine -2- base] sulfane Base } -2- phenyl-acetamides；
2- ({ 3,5- dicyano -4- ethyl -6- [4- (2- methoxy ethyl) -1,4- Diazesuberane -1- base] pyridine - 2- yl } sulfanyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxypropyl) -1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- [4- (6- { [carbamoyl (phenyl) methyl] sulfanyl } -3,5- dicyano -4- ethylpyridine -2- base) -1, 4- Diazesuberane -1- base] methyl acetate；
2- { [3,5- dicyano -4- cyclopropyl -6- (4- methyl -5- oxo -1,4- Diazesuberane -1- base) pyridine - 2- yl] sulfanyl } -2- phenyl-acetamides；
2- { [3,5- dicyano -4- cyclopropyl -6- (5- oxo -1,4- Diazesuberane -1- base) pyridine -2- base] sulphur Alkyl } -2- phenyl-acetamides；
2- { [3,5- dicyano -4- ethyl -6- (4- methyl -5- oxo -1,4- Diazesuberane -1- base) pyridine -2- Base] sulfanyl } -2- phenyl-acetamides；
2- { [3,5- dicyano -6- (1,4- Diazesuberane -1- base) -4- ethylpyridine -2- base] sulfanyl } -2- benzene Yl acetamide；
2- ({ 3,5- dicyano -6- [4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base] -4- (2,2,2- trifluoro Ethyl) pyridine -2- base } sulfanyl) -2- phenyl-acetamides；
(2R) -2- ({ 3,5- dicyano -4- ethyl -6- [4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base] pyrrole Pyridine -2- base } amino) -2- phenyl-acetamides；
2- ({ 6- [(3S) -3- amino-pyrrolidine -1- base] -3,5- dicyano -4- cyclopropyl pyridine -2- base } sulfanyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (2,9- diaza spiro [5.5] hendecane -9- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (hexahydro -1H- pyrrolo- [1,2-a] [1,4] diazacyclo heptantriene -2 (3H)-yl) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (2- methyl -2,9- diaza spiro [5.5] hendecane -9- base) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (2- (Cvclopropvlmethvl) -2,9- diaza spiro [5.5] hendecane -9- base) -4- ethyl Pyridine -2- base) sulfenyl) -2- phenylacetyl amine hydrochlorate；
2- ((3,5- dicyano -6- (4- (3- (dimethylamino) propyl) piperazine -1- base) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-3-yl) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；2,2,2- trifluoroacetic acid；
2- ((6- ([4,4'- joins piperidines] -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((6- (4- (2- amino-ethyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((6- (4- (3- aminopropyl) piperazine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (4- ((4- methylpiperazine-1-yl) methyl) piperidin-1-yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((6- (4- Acetylpiperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxyethyl) piperazine -1- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- [(3,5- dicyano -4- cyclopropyl -6- morpholino -2- pyridyl group) sulfanyl] -2- phenvl-acetamide；
2- ((6- (4- benzoyl-piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- ethyl -6- ((5S, 6S) -6- hydroxyl -1- (methyl sulphonyl) -1,8- diaza spiro [4.5] decyl- 8- yl) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4,4- difluoropiperdin -1- base) -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
(R) -2- ((3,5- dicyano -4- ethyl -6- ((R) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- (furans -2- base) -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((6- (4- amino -4- methyl piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) acetamide；
(2S) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- second Yl pyridines -2- base) piperidin-4-yl) propionamide；
2- ((6- (4- (3- amino oxetanes -3- carbonyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
4- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) tetrahydro -2H- pyrans -4- formamide；
2- ((6- (4- (4- amino tetrahydro -2H- pyrans -4- carbonyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base) -4-methoxypyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((6- ((2- amino-ethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((6- ((2- amino -2- oxoethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (3- hydroxy azetidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((2- hydroxyethyl) (methyl) amino) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) -2- methyl propanamide；
2- ((6- (4- (2- amino ethoxy) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxyl-oxethyl) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
Or its pharmaceutically acceptable salt or prodrug.
The prodrug of formula (Vbbr) is:
Biphosphate 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) pyrrolidin-3-yl ester；
Biphosphate 2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) (methyl) amino) ethyl ester；
Biphosphate 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) azetidine -3- base ester；
(2S) -2- amino -3 Methylbutanoic acid 2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- Dicyano -4- ethylpyridine -2- base) piperidin-4-yl) oxygroup) ethyl ester；
Biphosphate (S) -1- (6- (((S) -2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- second Yl pyridines -2- base) pyrrolidin-3-yl ester；
Biphosphate 2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) oxygroup) ethyl ester；With
Biphosphate 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) piperidin-4-yl ester；
Or its pharmaceutically acceptable salt.
Non- primary amide:
Suitably, the new formula of the present invention (Icr) compound is selected from:
2- amino-N- (1- (3,5- dicyano -4- ethyl -6- ((4- (N- methylmethylsulfonamido) benzyl) sulfenyl) pyrrole Pyridine -2- base) piperidin-4-yl) -2- methyl propanamide；
(R) -2- amino-N- (1- (3,5- dicyano -4- ethyl -6- ((4- (N- methylmethylsulfonamido) benzyl) sulphur Base) pyridine -2- base) piperidin-4-yl) propionamide；
N- (4- (((3,5- dicyano -4- ethyl -6- (methyl (2- (piperidin-1-yl) ethyl) amino) pyridine -2- base) sulphur Base) methyl) phenyl)-N- methyl methyl sulfonamide；
N- (4- (((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) methyl) benzyl Base) acetamide；
2- (4- amino piperidine -1- base) -6- ((4- (1,1- dioxidoisothiazolidin -2- base) benzyl) sulfenyl) -4- ethyl Pyridine -3,5- dimethoxy nitrile；
2- (4- amino piperidine -1- base) -6- ((4- (1,1- titanium dioxide -1,2- thiazine -2- base) benzyl) sulfenyl) -4- ethyl Pyridine -3,5- dimethoxy nitrile；
2- (4- amino piperidine -1- base) -4- ethyl -6- ((4- ((methyl sulphonyl) methyl) benzyl) sulfenyl) pyridine -3, 5- dimethoxy nitrile；
Methanesulfonic acid 4- (((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) methyl) Phenylester；
N- (4- (((3,5- dicyano -4- ethyl -6- (4- (isopropylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) Methyl) phenyl)-N- methyl methyl sulfonamide；
N- (4- (((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) methyl) benzene Base)-N- methyl methyl sulfonamide；
N- (4- ((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- base sulfenyl) first Base) benzyl) acetamide；
2- amino-N- (4- (((3,5- dicyano -6- ((2- (diethylamino) ethyl) (methyl) amino) -4- ethyl pyrrole Pyridine -2- base) sulfenyl) methyl) benzyl) acetamide；
Rel-2- amino-N- (4- (((6- (cis- -4- amino -3- fluorine resources -1- base) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) sulfenyl) methyl) benzyl) acetamide；
N- (4- (((3,5- dicyano -4- ethyl -6- (2- (pyrrolidin-1-yl methyl) morpholino) pyridine -2- base) sulphur Base) methyl) phenyl)-N- methyl methyl sulfonamide；
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) benzyl) acetamide；With
N- (4- (((3,5- dicyano -6- (3- ((dimethylamino) methyl) piperidin-1-yl) -4- ethylpyridine -2- base) Sulfenyl) methyl) phenyl)-N- methyl methyl sulfonamide；
Or its pharmaceutically acceptable salt or prodrug.
Suitably, the new formula of the present invention (Icr) compound is selected from:
N- (4- ((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- base sulfenyl) first Base) benzyl) acetamide；
2- (4- (amino methyl) benzyl sulfenyl) -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -3,5- Dimethoxy nitrile；
4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) methyl) the benzylcarbamate tert-butyl ester；
4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) methyl) benzamide；
2- ((4- (amino methyl) benzyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyrrole Pyridine -3,5- dimethoxy nitrile；
2- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) phenyl) acetic acid；
4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) methyl) benzoic acid；
2- (dimethylamino) -4- ethyl -6- (((6- oxo -1,6- dihydropyridine -3- base) methyl) sulfenyl) pyridine -3, 5- dimethoxy nitrile；
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) thiazol-2-yl) acetamide；
4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) methyl) benzsulfamide；
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) benzyl) acetamide；
(2- ((4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) methyl) benzyl) amino) -2- oxoethyl) t-butyl carbamate；
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) benzyl) methylsulfonamides；
2- amino-N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyrrole Pyridine -2- base) sulfenyl) methyl) benzyl) acetamide；
2- (4- amino piperidine -1- base) -6- (benzyl sulfenyl) -4- ethylpyridine -3,5- dimethoxy nitrile；
Acetic acid 4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) benzyl ester；
2- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) phenyl-acetamides；
2- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) phenyl)-N- methylacetamide；
4- ethyl -2- ((4- (hydroxymethyl) benzyl) sulfenyl) -6- (4- methyl-1,4- Diazesuberane -1- base) pyrrole Pyridine -3,5- dimethoxy nitrile；
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) benzyl) -2- hydroxyl acetamide；
Embodiment 87N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyrrole Pyridine -2- base) sulfenyl) methyl) benzyl) propionamide；
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) benzyl) isobutyramide；
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) benzyl) -3- methylbutyryl amine；
4- ethyl -2- ((4- (((2- hydroxyethyl) amino) methyl) benzyl) sulfenyl) -6- (4- methyl-1,4- diaza Cycloheptane -1- base) pyridine -3,5- dimethoxy nitrile；
N- (4- (((3,5- dicyano -6- (4- methyl-1,4- Diazesuberane -1- base) -4- (methylamino) pyridine - 2- yl) sulfenyl) methyl) benzyl) acetamide；
2- (((2- acetyl group -1,2,3,4- tetrahydroisoquinoline -6- base) methyl) sulfenyl) -6- (dimethylamino) -4- second Yl pyridines -3,5- dimethoxy nitrile；
2- ((4- cyanobenzyls) sulfenyl) -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -3,5- Dimethoxy nitrile；
2- amino-N- (1- (6- (benzyl sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl) acetyl Amine；
2- amino-N- (1- (6- (benzyl sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl) -2- first Base propionamide；
3- amino-N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyrrole Pyridine -2- base) sulfenyl) methyl) benzyl) propionamide；
(S) -2- amino-N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) Pyridine -2- base) sulfenyl) methyl) benzyl) propionamide；
(R) -2- amino-N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) Pyridine -2- base) sulfenyl) methyl) benzyl) propionamide；
1- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) benzyl) -3- ethyl urea；
1- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) benzyl) -3- phenylurea；
N- (4- (((3,5- dicyano -6- (4- methyl-1,4- Diazesuberane -1- base) -4- (methylsulfany) pyridine - 2- yl) sulfenyl) methyl) benzyl) acetamide；
(E) -3- (4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl) phenyl) Acrylic acid；
N- (4- (((3,5- dicyano -4- ethyl -6- ((2- hydroxyethyl) (methyl) amino) pyridine -2- base) sulfenyl) first Base) benzyl) acetamide；
4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) methyl)-N- methyl benzenesulfonamide；
N- (4- (((3,5- dicyano -4- ethyoxyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) methyl) benzyl) acetamide；
N- (4- (((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) methyl) benzyl Base) acetamide；
2- amino -3 Methylbutanoic acid (S) -2- ((1- (6- ((4- (acetylamino methyl) benzyl) sulfenyl) -3,5- dicyan Base -4- ethylpyridine -2- base) piperidin-4-yl) oxygroup) ethyl ester；
2- amino -3 Methylbutanoic acid (S) -2- ((6- ((4- (acetylamino methyl) benzyl) sulfenyl) -3,5- dicyano -4- Ethylpyridine -2- base) (methyl) amino) ethyl ester；
2- amino-N- (4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl) benzyl Base) acetamide；
4- ethyl -2- (4- methyl-1,4- Diazesuberane -1- base) -6- ((4- ((2- oxo-pyrrolidine -1- base) first Base) benzyl) sulfenyl) pyridine -3,5- dimethoxy nitrile；
2- ((4- (amino methyl) benzyl) sulfenyl) -6- (dimethylamino) -4- ethylpyridine -3,5- dimethoxy nitrile；
N- (4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl) phenyl) acetyl Amine；
N- (4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl) benzyl) -2- Hydroxyl acetamide；
3- amino-N- (4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl) benzyl Base) propionamide；
2- amino -3 Methylbutanoic acid (S) -1- (6- ((4- (acetylamino methyl) benzyl) sulfenyl) -3,5- dicyano -4- Ethylpyridine -2- base) azetidine -3- base ester；
N- (4- (((3,5- dicyano -4- ethyl -6- picoline -2- base) sulfenyl) methyl) benzyl) acetamide；
2- (4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl) -1H- pyrazoles - 1- yl) acetamide；
N- (4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl) phenyl) methyl Sulfonamide；
2- amino -3 Methylbutanoic acid (S) -1- (6- ((4- (acetylamino methyl) benzyl) sulfenyl) -3,5- dicyano -4- Ethylpyridine -2- base) piperidin-4-yl ester；
N- (1- (6- ((4- (acetylamino methyl) benzyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidines - 4- yl) acetamide；
2- (4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl) phenyl)-N- (2- hydroxyethyl) acetamide；
4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl)-N- (2- hydroxyl second Base) benzamide；
2- ((4- (1H- imidazoles -1- base) benzyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- Base) pyridine -3,5- dimethoxy nitrile；
2- ((4- cyano -3- methylbenzyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyrrole Pyridine -3,5- dimethoxy nitrile；
(4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) methyl) phenyl) t-butyl carbamate；
2- ((4- aminobenzyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -3,5- Dimethoxy nitrile；
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) phenyl) acetamide；
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) phenyl) methylsulfonamides；
2- (((6- aminopyridine -3- base) methyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- Base) pyridine -3,5- dimethoxy nitrile；
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) phenyl) -2- hydroxyl acetamide；
2- amino-N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyrrole Pyridine -2- base) sulfenyl) methyl) phenyl) acetamide；
N- (4- (((3,5- dicyano -4- ethyl -6- (3- oxypiperazin -1- base) pyridine -2- base) sulfenyl) methyl) benzyl Base) acetamide；
N- (4- (((3,5- dicyano -4- ethyl -6- (3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) methyl) benzyl Base) acetamide；
N- (4- (1- (3,5- dicyano -6- (4- (dimethylamino) piperidin-1-yl) -4- ethylpyridine -2- base sulfenyl) Propyl) benzyl) acetamide；
N- (5- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) pyridine -2- base) methylsulfonamides；
2- (6- (4- (acetylamino methyl) benzyl sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base sulfenyl) -2- benzene Yl acetamide；
4- ethyl -2- ((4- (pyridin-3-yl) benzyl) sulfenyl) -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine - 3,5- dimethoxy nitrile；
4- ethyl -2- ((4- (pyridin-4-yl) benzyl) sulfenyl) -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine - 3,5- dimethoxy nitrile；
2- amino-N- (1- (3,5- dicyano -4- ethyl -6- ((4- sulfamoylbenzyl) sulfenyl) pyridine -2- base) piperazine Pyridine -4- base) acetamide；
2- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) phenyl)-N- (2- hydroxyethyl) acetamide；
2- (((1H- indoles -5- base) methyl) sulfenyl) -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine - 3,5- dimethoxy nitrile；
4- (((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) methyl) benzene sulfonyl Amine；
2- ((benzo [d] [1,3] dioxole -5- ylmethyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- phenodiazine Trioxepane -1- base) pyridine -3,5- dimethoxy nitrile；
2- (((3,3- dimethoxy -2- oxoindoline -5- base) methyl) sulfenyl) -4- ethyl -6- (4- methyl-1, 4- Diazesuberane -1- base) pyridine -3,5- dimethoxy nitrile；
2- (((2,3- dioxo indoline -5- base) methyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- diazacyclo Heptane -1- base) pyridine -3,5- dimethoxy nitrile；
N- (4- (((6- (((4H-1,2,4- triazole -3- base) methyl) (methyl) amino) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) sulfenyl) methyl) benzyl) acetamide；
4- ethyl -2- ((4- (pyridine -2- base) benzyl) sulfenyl) -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine - 3,5- dimethoxy nitrile；
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) phenyl)-N- methylacetamide；
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) phenyl)-N- methyl methyl sulfonamide；
4- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base sulfenyl) Methyl) phenylboric acid；
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) benzyl) -2- (methylamino) acetamide；
2- ((4- amino -3- luorobenzyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyrrole Pyridine -3,5- dimethoxy nitrile；
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) -2- fluorophenyl) methylsulfonamides；
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) -2- fluorophenyl) acetamide；
2- (4- amino piperidine -1- base) -4- ethyl -6- (((1- (2- hydroxyethyl) -1H- pyrazoles -4- base) methyl) sulphur Base) pyridine -3,5- dimethoxy nitrile；
N- (4- (((3,5- dicyano -4- ethyl -6- (3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) methyl) benzyl Base) -2- hydroxyl acetamide；
N- (4- (((6- ((2- amino -2- oxoethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) Sulfenyl) methyl) benzyl) -2- hydroxyl acetamide；
2- (4- (2- (dimethylamino) ethyoxyl) benzyl sulfenyl) -4- ethyl -6- (4- methyl-1,4- diaza cycloheptyl Alkane -1- base) pyridine -3,5- dimethoxy nitrile；
4- ethyl -2- (4- methyl-1,4- Diazesuberane -1- base) -6- ((4- (methyl sulphonyl) benzyl) sulfenyl) Pyridine -3,5- dimethoxy nitrile；
2- (4- amino piperidine -1- base) -6- (((1- (2,3- dihydroxypropyl) -1H- pyrazoles -4- base) methyl) sulfenyl) - 4- ethylpyridine -3,5- dimethoxy nitrile；
4- ethyl -2- (4- methyl-1,4- Diazesuberane -1- base) -6- ((4- (4- methylpiperazine-1-yl) benzyl) Sulfenyl) pyridine -3,5- dimethoxy nitrile；
4- ethyl -2- (4- methyl-1,4- Diazesuberane -1- base) -6- ((4- (((2- oxo-pyrrolidine -3- base) ammonia Base) methyl) benzyl) sulfenyl) pyridine -3,5- dimethoxy nitrile；
2- (((1H- benzo [d] imidazoles -5- base) methyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- diaza cycloheptyl Alkane -1- base) pyridine -3,5- dimethoxy nitrile；
4- ethyl -2- (4- methyl-1,4- Diazesuberane -1- base) -6- (4- (sulfonyloxy methyl ylmethyl) dibenzylsulfide Base) pyridine -3,5- dimethoxy nitrile；
2- { [3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base] sulfanyl } -2- phenyl-acetamides；
N- (4- (((3,5- dicyano -4- ethyl -6- (methyl (2- (neopentyl amino) ethyl) amino) pyridine -2- base) Sulfenyl) methyl) phenyl)-N- methyl methyl sulfonamide；
N- (4- (((3,5- dicyano -4- ethyl -6- ((2- ((2- methoxy ethyl) (methyl) amino) ethyl) (methyl) Amino) pyridine -2- base) sulfenyl) methyl) phenyl)-N- methyl methyl sulfonamide；
N- (4- (((3,5- dicyano -4- ethyl -6- (methyl (2- (methylamino) ethyl) amino) pyridine -2- base) sulphur Base) methyl) phenyl)-N- methyl methyl sulfonamide；
N- (4- (((3,5- dicyano -4- ethyl -6- ((2- ((2- methoxy ethyl) amino) ethyl) (methyl) amino) Pyridine -2- base) sulfenyl) methyl) phenyl)-N- methyl methyl sulfonamide；
N- (4- (((3,5- dicyano -4- ethyl -6- (methyl (2- ((1- methylcyclopropyl groups) amino) ethyl) amino) pyrrole Pyridine -2- base) sulfenyl) methyl) phenyl)-N- methyl methyl sulfonamide；
N- (4- (((3,5- dicyano -6- ((2- (dimethylamino) ethyl) (methyl) amino) -4- ethylpyridine -2- Base) sulfenyl) methyl) phenyl)-N- methyl methyl sulfonamide；
N- (4- (((6- ((2- amino-ethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) first Base) phenyl)-N- methyl methyl sulfonamide；
2- (4- amino piperidine -1- base) -4- ethyl -6- ((4- ((methyl sulphonyl) methyl) benzyl) sulfenyl) pyridine -3, 5- dimethoxy nitrile；
N- (4- (((3,5- dicyano -4- ethyl -6- ((2- ((2- fluoro ethyl) amino) ethyl) (methyl) amino) pyridine - 2- yl) sulfenyl) methyl) phenyl)-N- methyl methyl sulfonamide；
2- amino-N- (4- (((3,5- dicyano -6- ((2- (diethylamino) ethyl) (methyl) amino) -4- ethyl pyrrole Pyridine -2- base) sulfenyl) methyl) benzyl) acetamide；
4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) methyl)-N- (1H- pyrazoles -4- base) benzamide；
Rel-2- amino-N- (4- (((6- (cis- -4- amino -3- fluorine resources -1- base) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) sulfenyl) methyl) benzyl) acetamide；
N- (4- (((3,5- dicyano -4- ethyl -6- (4- (isopropylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) Methyl) phenyl)-N- methyl methyl sulfonamide；
N- (4- (((3,5- dicyano -4- ethyl -6- (4- ((2- methoxy ethyl) amino) piperidin-1-yl) pyridine -2- Base) sulfenyl) methyl) phenyl)-N- methyl methyl sulfonamide；
N- (4- (((3,5- dicyano -4- ethyl -6- (4- (neopentyl amino) piperidin-1-yl) pyridine -2- base) sulfenyl) Methyl) phenyl)-N- methyl methyl sulfonamide；
N- (4- (((3,5- dicyano -4- ethyl -6- (methyl (2- (pyrrolidin-1-yl) ethyl) amino) pyridine -2- base) Sulfenyl) methyl) phenyl)-N- methyl methyl sulfonamide；
N- (4- (((3,5- dicyano -6- (2- ((dimethylamino) methyl) morpholino) -4- ethylpyridine -2- base) sulphur Base) methyl) phenyl)-N- methyl methyl sulfonamide；
2- amino-N- (1- (3,5- dicyano -4- ethyl -6- ((4- (N- methylmethylsulfonamido) benzyl) sulfenyl) pyrrole Pyridine -2- base) piperidin-4-yl) -2- methyl propanamide；
N- (4- (((3,5- dicyano -6- (4- (cyclopropylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) Methyl) phenyl)-N- methyl methyl sulfonamide；
N- (4- (((3,5- dicyano -4- ethyl -6- (2- (pyrrolidin-1-yl methyl) morpholino) pyridine -2- base) sulphur Base) methyl) phenyl)-N- methyl methyl sulfonamide；
N- (4- (((3,5- dicyano -4- ethyl -6- (methyl (2- (piperidin-1-yl) ethyl) amino) pyridine -2- base) sulphur Base) methyl) phenyl)-N- methyl methyl sulfonamide；
N- (4- (((3,5- dicyano -6- ((2- (diethylamino) ethyl) (methyl) amino) -4- ethylpyridine -2- Base) sulfenyl) methyl) phenyl)-N- methyl methyl sulfonamide；
N- (4- (((3,5- dicyano -6- (2- ((diethylamino) methyl) morpholino) -4- ethylpyridine -2- base) sulphur Base) methyl) phenyl)-N- methyl methyl sulfonamide；
N- (4- (((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- base) sulfenyl) Methyl) phenyl)-N- methyl methyl sulfonamide；
(R) -2- amino-N- (1- (3,5- dicyano -4- ethyl -6- ((4- (N- methylmethylsulfonamido) benzyl) sulphur Base) pyridine -2- base) piperidin-4-yl) propionamide；
(S) -2- amino-N- (1- (3,5- dicyano -4- ethyl -6- ((4- (N- methylmethylsulfonamido) benzyl) sulphur Base) pyridine -2- base) piperidin-4-yl) propionamide；
N- (4- (((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) methyl) benzene Base)-N- methyl methyl sulfonamide；
2- amino-N- (1- (3,5- dicyano -4- ethyl -6- ((4- (N- methylmethylsulfonamido) benzyl) sulfenyl) pyrrole Pyridine -2- base) piperidin-4-yl) acetamide；
N- (4- (((6- (2- (amino methyl) morpholino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) methyl) Phenyl)-N- methyl methyl sulfonamide；
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) phenyl) the fluoro- N- methyl methyl sulfonamide of -1-；
N- (4- (((3,5- dicyano -4- ethyl -6- (2- ((methylamino) methyl) morpholino) pyridine -2- base) sulfenyl) Methyl) phenyl)-N- methyl methyl sulfonamide；
N- (4- (((3,5- dicyano -6- (3- ((dimethylamino) methyl) piperidin-1-yl) -4- ethylpyridine -2- base) Sulfenyl) methyl) phenyl)-N- methyl methyl sulfonamide；
2- (4- amino piperidine -1- base) -6- ((4- (1,1- dioxidoisothiazolidin -2- base) benzyl) sulfenyl) -4- ethyl Pyridine -3,5- dimethoxy nitrile；
2- (4- amino piperidine -1- base) -6- ((4- (1,1- titanium dioxide -1,2- thiazine -2- base) benzyl) sulfenyl) -4- ethyl Pyridine -3,5- dimethoxy nitrile；
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) phenyl) -1,1- difluoro-N-methyl methylsulfonamides；
2- ((4- (1,1- dioxidoisothiazolidin -2- base) benzyl) sulfenyl) -4- ethyl -6- (4- (neopentyl amino) piperazine Pyridine -1- base) pyridine -3,5- dimethoxy nitrile；
2- ((4- (1,1- titanium dioxide -1,2- thiazine -2- base) benzyl) sulfenyl) -4- ethyl -6- (4- (neopentyl amino) piperazine Pyridine -1- base) pyridine -3,5- dimethoxy nitrile；
Methanesulfonic acid 4- (((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) methyl) Phenylester；
(R) -2- amino-N- ((1- (3,5- dicyano -4- ethyl -6- ((4- (N- methylmethylsulfonamido) benzyl) sulphur Base) pyridine -2- base) pyrrolidin-3-yl) methyl) acetamide；
(S) -2- amino-N- ((1- (3,5- dicyano -4- ethyl -6- ((4- (N- methylmethylsulfonamido) benzyl) sulphur Base) pyridine -2- base) pyrrolidin-3-yl) methyl) acetamide；
N- (4- (1- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) ethyl) benzene Base)-N- methyl methyl sulfonamide；
N- (4- (((6- (4- amino piperidine -1- base) -3,5- dicyano -4-methoxypyridine -2- base) sulfenyl) methyl) benzene Base)-N- methyl methyl sulfonamide；With
N- (4- (((3,5- dicyano -4- ethyl -6- (4- ((2- hydroxyethyl) amino) piperidin-1-yl) pyridine -2- base) Sulfenyl) methyl) phenyl)-N- methyl methyl sulfonamide；
Or its pharmaceutically acceptable salt or prodrug.
It will be appreciated by those skilled in the art that the pharmaceutically acceptable salt of formula (I) compound can be prepared.In fact, at this In some embodiments of invention, the pharmaceutically acceptable salt of formula (I) compound can be better than corresponding free or non-salinization Close object.Therefore, the invention further relates to the pharmaceutically acceptable salts of formula (I) compound.The invention further relates to free or non-salinization Formula (I) compound.
The pharmaceutically acceptable salt of the compound of the present invention is readily prepared by those skilled in the art.
Representative pharmaceutically acceptable acid-addition salts include but is not limited to 4- acetaminobenzoic acid salt, acetate, Adipate, alginates, ascorbate, aspartate, benzene sulfonate (benzenesulfonate, besylate), benzene Formates, disulfate, biatrate, butyrate, Ca-EDTA, camphor hydrochlorate, camsilate (camphorsulfonate, camsylate), caprate (ten carbonate), caproate (caproate, hexanoate), octanoic acid Salt (caprylate, octanoate), cinnamate, citrate, cyclamate, digluconate, 2,5- dihydroxy Yl benzoic acid salt, disuccinate, lauryl sulfate (dodecylsulfate, estolate), edetate (edetate, ethylenediaminetetraacetate), lauryl sulfate (estolate, lauryl sulfate), Ethane -1,2- disulfonate (ethanedisulphonate), esilate (ethanesulfonate, esylate), formates, fumaric acid Salt, galactolipin hydrochlorate (mucate), gentisate (2,5-dihydroxybenzoic acid salt), gluceptate (glucoheptonate, Gluceptate), gluconate, glucuronate salt, glutamate, glutarate, glycerophosphate, glycollate, oneself Base M-phthalic acid salt, hippurate, breathe out amine (hydrabamine) (N, N'- bis- (dehydroabietyl)-ethylenediamine), hydrobromate, Hydrochloride, hydriodate, Hydroxynaphthoate, isobutyrate, lactate, lactobionate, laruate, malate, horse Come hydrochlorate, malonate, mandelate, mesylate (methanesulfonate, mesylate), Methylsulfate, glactaric acid Salt, naphthalene -1,5- disulfonate (napadisilate), naphthalene-2-sulfonic acid salt (naphthalene sulfonate), nicotinate, nitrate, oleate, palm fibre Palmitic acid hydrochlorate, sulfanilate, PAS salt, embonate (pamoate, embonate), pantothenate, pectin Hydrochlorate, persulfate, phenylacetate, phenylethylmalonylurea salt, phosphate, Polygalacturonate, propionate, to toluene sulphur Hydrochlorate (p-toluenesulfonate, tosylate), pyroglutamate, acetonate, salicylate, sebacate, tristearin Hydrochlorate, subacetate, succinate, sulfamate, sulfate, tannate, tartrate, teoclate (teoclate, 8-chlorotheophyllinate), rhodanate, triethiodide compound, undecylate, undecylenate And valerate.
Representative pharmaceutically acceptable base addition salts include but is not limited to aluminium, 2- amino -2- (hydroxymethyl) -1,3- Propylene glycol (TRIS, tromethamine), arginine, phenylethylbenzylamine (N- benzyl-1-phenylethylamine), benzyl star (N, N '-dibenzyl second two Amine), double-(2- hydroxyethyl) amine, bismuth, calcium, chloroprocanine, choline, clemizole (1- p-chlorobenzyl -2- pyrrolidines -1'- Ylmethylbenzimidazole), cyclohexylamine, benzhydryl ethylenediamine, diethylamine, diethyl triamine, dimethylamine, dimethylethanolamine, Dopamine, ethanol amine, ethylenediamine, L-Histidine, iron, isoquinolin, 4- methylquinoline, lithium, lysine, magnesium, meglumine (N- methyl Aminoglucose), piperazine, piperidines, potassium, procaine, quinine, quinoline, sodium, strontium, tert-butylamine and zinc.
Formula (I) compound can be containing one or more asymmetric centers (also referred to as chiral centre), therefore can be used as Individual enantiomter, diastereoisomer or other stereoisomeric forms in any ratio, or exist as its mixture.Chiral centre, Such as asymmetric carbon atom, it can reside in substituent group such as alkyl.It is in formula (I) compound or shown in this article any when being present in When the spatial chemistry of chiral centre in chemical structure is not specified, the structure be intended to cover all individual stereoisomers and its All mixtures.Therefore, formula (I) compound containing one or more chiral centres may be used as racemic mixture, mapping The mixture that body is enriched with or the single stereoisomer as enantiomer-pure.
Formula (I) compound and its pharmaceutically acceptable salt can containing the compound of isotope labelling, with formula (I) and Those described below is identical, in addition to one or more atoms are different from atomic mass or mass number usually in nature The atomic mass of middle discovery or the atom of mass number replace.The example of this isotope include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, The isotope of iodine and chlorine, such as2H、3H、11C、13C、14C、15N、17O、18O、31P、32P、35S、18F、36Cl、123I and125I。
The compound of isotope labelling, such as incorporation radioactive isotope is such as3H or14The compound of C, can be used for drug and/ Or substrate tissue measure of spread.Tritium is (i.e.3H) and carbon-14 (i.e.14C) isotope is especially excellent because of its easily prepared and detectability Choosing.11C and18F isotope is particularly useful in PET (positron emission computerized tomography), and125I isotope is in SPECT (monochromatic light Sub- emission computed tomography) in it is particularly useful, the two can be used in Brian Imaging.In addition, with heavier isotope such as deuterium (i.e.2H some treatment advantages can be provided by) replacing, this is because higher metabolic stability, such as prolonged half-life in vivo or Volume requirements are reduced, therefore in some cases may be preferred.The compound of isotope labelling usually can be by with appearance The reagent of the isotope labelling easily obtained replaces isotope-labeled reagent to prepare.
The compound of formula (I) can also include double bond or other geometry asymmetric centers.Exist in the formula that is not specified by (I) Geometry asymmetric center or any chemical structure shown in this article spatial chemistry in the case where, which is intended to include trans- (E) geometric isomer, cis- (Z) geometric isomer and its all mixtures.Similarly, all tautomeric forms are also included within In formula (I), no matter these tautomers, which are balances, exists or mainly exists in one form.
The compound of the present invention can exist in solid or liquid form.In solid form, the compound of the present invention can To exist with completely amorphous to the continuous solid-state being fully crystallized.Term " amorphous " refers to that material lacks length on a molecular scale The state of Cheng Youxu, and temperature is depended on, the physical property of solid or liquid can be shown.In general, this material cannot Unique X-ray diffractogram is provided, although and show the property of solid, more formally it is described as liquid.When heated, The variation from solid to liquid property occurs, it is characterised in that the variation of state, usually second order (" glass transition ").Term " crystallization " refers to solid phase, and wherein material has regular internal structure on a molecular scale, and provides to have and determine peak Unique X-ray diffractogram.When heated sufficiently, this material will also show the property of liquid, but from solid to liquid Variation be characterized in that phase transformation, usually level-one (" fusing point ").
The compounds of this invention can have the ability crystallized in the form of more than one, this is a kind of feature, referred to as polymorphism (" polymorphic ").Polymorphism usually can be used as the response of the variation to temperature or pressure or both and occur, and can be with Caused by the variation of crystallization process.Polymorph can be distinguished by various physical features known in the art, such as X-ray Diffraction pattern, solubility and fusing point.
Formula (I) compound can exist with solvated and unsolvated form.As used herein, term " solvate " refers to By the compound for the varying chemical metering that solute (in the present invention, formula (I) compound or salt) and solvent are formed.For the present invention Purpose, these solvents may not interfere the bioactivity of solute.It will be understood by those skilled in the art that pharmaceutically acceptable Solvate can form crystalline compounds, and wherein solvent molecule is integrated in lattice during crystallization.The solvent molecule of incorporation It can be hydrone or non-aqueous solution, such as ethyl alcohol, isopropanol, DMSO, acetic acid, ethanol amine and ethyl acetate molecule.With moisture The crystalline lattice structure that son combines is commonly referred to as " hydrate ".Hydrate includes the hydrate of stoichiometry and contains variable The composition of water.
It shall yet further be noted that formula (I) compound can form tautomer." tautomer " refers to specific compound structure The compound of interchangeable form, and the displacement of hydrogen atom and electronics is different.Therefore, two structures can pass through pi-electron and original The movement of sub (usually H) and be in equilibrium state.For example, enol and ketone are tautomers because they pass through with acid or Alkali process and quickly mutually convert.It should be understood that all tautomers of the compounds of this invention and the mixture of tautomer It is included in the range of the compounds of this invention.
Although the various aspects of each variable have usually individually been listed above, the present invention is including several in wherein formula (I) A or each aspect is selected from those of each aspect listed above compound.Therefore, the present invention is intended to include each variables Combination in all aspects.
Definition
It should be appreciated that unless the context requires otherwise, it is otherwise defined below to be suitable for above-mentioned each chemical formula and these arts All examples of language.
" alkyl " refers to the hydrocarbon chain with " member atoms " specified number.For example, C1-C6Alkyl refers to 1 to 6 The alkyl of member atoms.Alkyl can be saturation, unsaturated, linear chain or branched chain.Representative branched alkyl has one A, two or three branches.Alkyl includes but is not limited to: methyl, ethyl, vinyl, propyl (n-propyl and isopropyl), butylene Base, butyl (normal-butyl, isobutyl group and tert-butyl), amyl and hexyl.
" alkoxy " refers to-O- alkyl, wherein " alkyl " is as defined herein.For example, C1-C4Alkoxy refers to 1-4 The alkoxy of a carbon atom.The example of this kind of group includes but is not limited to: methoxyl group, ethyoxyl, propoxyl group, butoxy and tertiary fourth Oxygroup.
" aryl " refers to aromatic hydrocarbons ring system.Aryl is that have the monocycle of five to 14 ring members atoms, bicyclic and three in total Ring ring system, wherein at least one ring system are aromatics, and wherein each ring in system contains 3 to 7 member atoms, such as But it is not limited to: phenyl, indane, naphthalene, tetrahydronaphthalene and biphenyl.Suitably, aryl is phenyl.
Unless otherwise defined, " naphthenic base " refers to the saturated or unsaturated non-aromatic hydrocarbon ring with 3-7 carbon atom.Ring Alkyl is monocycle or spiral ring system.For example, C3-C7Naphthenic base refers to the naphthenic base with 3 to 7 member atoms.It is used herein The example of naphthenic base includes but is not limited to: cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, cyclobutane base, cyclopentenyl, cyclohexene Base, spiral shell heptyl and suberyl.Suitably, naphthenic base is selected from: cyclopropyl, cyclopenta and cyclohexyl.
" heteroaryl " refers to containing 1 to 7 carbon atom and containing 1 to 4 independently selected from the heteroatomic of nitrogen, oxygen and sulphur Monocyclic aromatic 4-8 member ring, condition are when carbon atom number is 3, and aromatic ring contains at least two hetero atoms, or refers to such aromatic ring It is condensed with one or more rings, such as heteroaryl ring, aromatic ring, heterocycle or cycloalkyl ring.Contain more than one heteroatomic heteroaryl Contain different hetero atoms.Heteroaryl includes but is not limited to: benzimidazolyl, benzothiazolyl, benzothienyl, benzene And pyrazinyl, benzotriazole base, phentriazine base, benzo [1,4] dioxane base, benzofuranyl, 9H-a- carboline Base, cinnoline base, furyl, imidazole radicals, oxazolyl, indazolyl, indolizine base, indyl, isoindolyl, isothiazolyl, isoquinolin Base, isoxazolyl, indolizine base, phthalazinyl, oxazolyl, oxo thiadiazolyl group, oxadiazoles base, phthalazinyl, pyridyl group, pyrroles Base, purine radicals, dish piperidinyl, phenazinyl, pyrazolyl, pyrazolopyrimidine base, Pyrazolopyridine base, pyrroles's piperazine base (pyrrolizinyl), pyridazinyl, pyrazinyl, pyrimidine radicals, quinoxalinyl, quinazolyl, quinolyl, quinazinyl, thienyl, benzene Sulfenyl, triazolyl, triazine radical, tetrazolo pyrimidine radicals, triazolopyrimidinyl, tetrazole radical, thiadiazolyl group, thiazolyl and thiazolidine Base.Suitably, heteroaryl is selected from: furyl, pyrazolyl, pyrrole radicals, imidazole radicals, isoxazolyl, isothiazolyl, oxazolyl, three Oxazolyl, thiazolyl and thienyl.Suitably, heteroaryl is pyridyl group or imidazole radicals.Suitably, heteroaryl is pyridyl group.
Unless otherwise defined, " heterocycle " used herein or " Heterocyclylalkyl " refer to containing 4 to 12 member atoms Saturated or unsaturated non-aromatic ring, wherein 1 to 11 is carbon atom and 1 to 6 is the miscellaneous original for being independently selected from nitrogen, oxygen and sulphur Son.Contain different hetero atoms containing more than one heteroatomic Heterocyclylalkyl.This ring can optionally with it is one or more its His " heterocycle " ring, aromatic ring, heteroaryl ring or cycloalkyl ring are condensed.This ring can be that bridging is bicyclic or loop coil." heterocycle " group Example include but is not limited to: 1,4- Diazesuberane base, azetidinyl, oxetanyl, 1,4- dioxane Hexyl, 1,3- dioxane base, pyrrolidinyl, pyrrolidin-2-one base, piperidyl, piperazinyl, piperazine-2,5-dione Base, morpholinyl, dihydro pyranyl, dihydro cinnoline base, dihydropyridine base, THP trtrahydropyranyl, 2,3 dihydro furan base, 2,3- dihydro Benzofuranyl, dihydro-isoxazole base, tetrahydro oxazolyl, tetrahydrofuran base, tetrahydro-thiazoles base, tetrahydro thiazinyl, tetrahydric thiapyran Base, tetrahydro-thienyl, dihydro-quinoxaline base, tetrahydroquinoxaline base, tetrahydro isoquinolyl, tetrahydro pyridyl, Tetrahydrocarboline base, 2, 9- diaza spiro [5.5] undecyl, 1,8- diaza spiro [4.5] decyl, 2,8- diaza spiro [4.5] decyl, hexahydropyrrolo And -1,4- Diazesuberane base, 1- oxa- -6- azaspiro [3.4] octyl, 5- oxa- -2- azaspiro [3.4] octyl, 1,7- diaza spiro [3.5] nonyl, 2,7- diaza spiro [3.5] nonyl, 2,6- diaza spiro [3.4] octyl, 1,8- Diaza spiro [4.5] decyl and 8- azabicyclo [3.2.1] octyl.Suitably, heterocycle is selected from: Isosorbide-5-Nitrae-Diazesuberane Base, azetidinyl, oxetanyl, pyrrolidinyl, dihydropyridine base, piperidyl, piperazinyl, morpholinyl, tetrahydro are different Quinolyl, THP trtrahydropyranyl, 2,9- diaza spiro [5.5] undecyl, 1,8- diaza spiro [4.5] decyl, 2,8- diaza Spiral shell [4.5] decyl, hexahydropyrrolo simultaneously -1,4- Diazesuberane base, 1- oxa- -6- azaspiro [3.4] octyl, 5- oxa- - 2- azaspiro [3.4] octyl, 1,7- diaza spiro [3.5] nonyl, 2,7- diaza spiro [3.5] nonyl, 2,6- phenodiazine Miscellaneous spiral shell [3.4] octyl, 1,8- diaza spiro [4.5] decyl and 8- azabicyclo [3.2.1] octyl.
" hetero atom " refers to nitrogen, sulphur or oxygen atom.
" halogen " and " halogen " refers to fluorine, chlorine, bromine or iodine atom.
Term " sulfydryl " as used herein refers to group-SH.
Term " oxo " as used herein refers to group=O.
Term " hydroxyl " as used herein refers to group-OH.
Term " amino " as used herein refers to group-NH2。
Term " amino carbonyl " as used herein refers to group-C (O) NH2。
Term " guanidine radicals " as used herein refers to group-NHC (=NH) NH2。
Term " carboxyl " as used herein refers to group-C (O) OH.
Term " cyano " as used herein refers to group-CN.
Term " prodrug " as used herein refers to that metabolism in vivo generates the compound of bioactive compound.It is this to have more The compound of bioactivity is referred to herein as " reactive compound ".The example of prodrug of the invention is the chemical combination of embodiment 151 Object.The example of corresponding reactive compound is the compound of embodiment 147.
Term " reactive compound " as used herein refers to that compound inhibits the activity of DNMT1 suitably to refer to conduct The compound of the selective depressant of DNMT1.
As used herein, term " selectivity ", when referring to chemical compound, suitably, reactive compound of the invention, Mean that, compared to DNMT3A or DNMT3B, the compound is surveyed as the inhibitor of DNMT1 in Breaklight as described herein More than 30 times activity are shown in fixed or similar measurement, suitably more than 50 times activity, suitably active more than 100 times IC50。
Term " compound A " as used herein refers to: 2- { [3,5- dicyano -6- (dimethylamino) -4- ethylpyridine - 2- yl] sulfanyl } -2- phenyl-acetamides, the compound of embodiment 3.
As used herein, make in symbol and convention and contemporary scientific literature used in these methods, scheme and embodiment Symbol is consistent with convention, for example, Journal of the American Chemical Society or Journal of Biological Chemistry.Standard single-letter or trigram abbreviation are commonly used in indicating amino acid residue, unless otherwise saying Bright, otherwise they are assumed L- configuration.Unless otherwise stated, all raw materials derive from commercial supplier and without into The purifying of one step can be used.Specifically, abbreviation can use in embodiment and the whole instruction below:
Ac (acetyl group)；
Ac2O (acetic anhydride)；
A-CN (acetonitrile)；
AIBN (azo is bis- (isobutyronitrile))；
BINAP (bis- (the diphenylphosphino) -1,1'- dinaphthalenes of 2,2'-)；
BMS (borane dimethyl sulphide complex compound)；
Bn (benzyl)；
Boc (tertbutyloxycarbonyl)；
Boc2O (di-tert-butyl dicarbonate)；
BOP (three (dimethylamino) phosphorus hexafluorophosphate of benzotriazole -1- base oxygroup)；
CAN (ammonium ceric nitrate)；
Cbz (benzyloxycarbonyl)；
CSI (chlorosulphonyl isocyanate)；
CSF (cesium fluoride)；
DABCO (1,4- diazabicyclo [2.2.2] octane)；
DAST ((diethylamino) sulfur trifluoride)；
DBU (11 carbon -7- alkene of 1,8- diazabicyclo [5.4.0])；
DCC (dicyclohexylcarbodiimide)；
DCE (1,2- dichloroethanes)；
DCM (methylene chloride)；
DDQ (the chloro- 5,6- dicyano -1,4- benzoquinones of 2,3- bis-)；
ATP (atriphos)；
(two -1,3,2- dioxa boron of 4,4,4', 4', 5,5,5', 5'- prestox -2,2'- is miscellaneous for bis- (pinacol combined) two boron Pentamethylene)；
BSA (bovine serum albumin(BSA))；
C18 (refers to the 18- carbon alkyl in HPLC stationary phase on silicon)
CH3- CN (acetonitrile) Cy (cyclohexyl)；
DCM (methylene chloride)；
DIEA (diisopropylethylamine)；
DIPEA (Xu Nixi alkali, N- ethyl-N- (1- Methylethyl) -2- propylamine)；
Dioxanes (1,4- dioxanes)；
DMAP (4-dimethylaminopyridine)；
DME (1,2- dimethoxy-ethane)；
DMEDA (N, N '-dimethyl ethylenediamine)；
DMF (N,N-dimethylformamide)；
DMSO (dimethyl sulfoxide)；
DPPA (diphenyl phosphate azide)；
EDC (N- (3- dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride)；
EDTA (ethylenediamine tetra-acetic acid)；
EtOAc (ethyl acetate)；
EtOH (ethyl alcohol)；
Et2O (ether)；
HEPES (4- (2- hydroxyethyl) -1- piperazinyl ethanesulfonic acid)；
HATU (O- (7- azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethylHexafluorophosphate)；
HOAt (1- hydroxyl -7- azepine benzotriazole)；
HOBt (I-hydroxybenzotriazole)；
HOAc (acetic acid)；
HPLC (high pressure liquid chromatography)；
HMDS (two silicon substrate amido of hexamethyl)；
Xu Nixi alkali (N, N- diisopropylethylamine)；
IPA (isopropanol)；
Indoline (2,3- dihydro -1H- indoles)；
KHMDS (potassium hexamethyldisilazide)；
LAH (lithium aluminium hydride reduction)；
LDA (lithium diisopropylamine)；
LHMDS (hexamethyldisilazide lithium)；
MeOH (methanol)；
MTBE (methyl tertiary butyl ether(MTBE))；
McM (micro-molar concentration)；
MCPBA (metachloroperbenzoic acid)；
NaHMDS (sodium hexamethyldisilazide)；
NCS (N-chloro-succinimide)；
NBS (N- bromine succinimide)；
PE (petroleum ether)；
Pd2(dba)3(tris(dibenzylideneacetone) dipalladium (0)；
Pd(dppf)Cl2.DCM complex compound ([1,1 '-bis- (diphenylphosphino) ferrocene] palladium chloride (II) dichloromethane Alkane complex compound)；
PyBOP (hexafluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole alkyl phosphorus)；
PyBrOP (tripyrrole alkane base phosphonium bromide hexafluorophosphate)；
RPHPLC (reverse-phase HPLC)；
RT (room temperature)；
Sat. (saturation)；
SFC (supercritical fluid chromatography)；
SGC (silica gel chromatograph)；
SM (starting material)；
TLC (thin-layer chromatography)；
TEA (triethylamine)；
TEMPO (2,2,6,6- tetramethyl-piperidyl 1- oxygroups, free radical)；
TFA (trifluoroacetic acid)；
THF (tetrahydrofuran)；With
Ts-Cl (paratoluensulfonyl chloride).
It is ether when referring to ether, salt water refers to the NaCl aqueous solution of saturation.
Compound preparation
Formula (I) compound is prepared using conventional methodology of organic synthesis.Suitable synthetic route is in following General reactions side It is described in case.All raw materials are all commercially available, or are easy to be prepared by those skilled in the art from marketable material.
It will be understood by those skilled in the art that if substituent group as described herein and synthetic method as described herein are inconsistent, Then substituent group can be protected with the appropriate protection base to stable reaction conditions.It can remove and protect in the suitable position in reaction sequence Group is protected, to provide required intermediate or target compound.Suitable blocking group and this suitable blocking group of use The method of protection and deprotection different substituents is well known to those skilled in the art.The example be found in T.Greene and P.Wuts, Protecting Groups in Organic Synthesis (the 4th edition), John Wiley&Sons, NY (2006).In some cases, substituent group can be selected especially to have reactivity under the reaction conditions employed.In these feelings Under condition, selected substituent group is converted another substituent group by reaction condition, the substituent group can be used as intermediate compound or Required substituent group in target compound.
Scheme 1
In some cases, the intermediate of formula 13 is used to obtain the intermediate of formula 4, as shown in scheme 2, and is used for scheme 1 and scheme 2 shown in subsequent step.
Scheme 2
In other cases, the intermediate of formula 13 is for obtaining 16 compound of formula, be used to obtain in the next steps as 18 compound of formula described in scheme 3.
Scheme 3
In some cases, the compound of formula 19 and 20 is for obtaining 21 compound of formula as described in scheme 4.
Scheme 4
Pass through the compound of synthetic route preparation formula 24 shown in scheme 5.The intermediate of formula 22 is commercially available chemical combination Object may or may not be single enantiomer.When 22 compound of formula is single enantiomer, the chemical combination of corresponding formula 23 and formula 24 Object is also such.
Scheme 5
For 26 compound of formula, as shown in scheme 6, the intermediate of formula 14 and the intermediate of formula 25 are used.In formula 25 Mesosome is commercially available or is synthesized using the conventional methodology of organic synthesis that can be replicated by any technical staff.
Scheme 6
Or the compound for formula 26, the intermediate of formula 14 and the intermediate of formula 27 are used as in scheme 7.Formula 27 intermediate is commercially available or is synthesized using the conventional methodology of organic synthesis that can be replicated by any technical staff.
Scheme 7
Pass through the compound of synthetic route preparation formula 33 and 34 shown in scheme 8.Intermediate 28 and 29 is commercially available Compound.The intermediate of formula 31 is business or is synthesized using the conventional methodology of organic synthesis that can be replicated by any technical staff.
Scheme 8
Pass through 40 compound of synthetic route preparation formula shown in scheme 9.Intermediate 35 and 36 is commercially available compound. The intermediate of formula 31 is business or is synthesized using the conventional methodology of organic synthesis that can be replicated by any technical staff.
Scheme 9
Pass through 43 compound of synthetic route preparation formula shown in scheme 10.Intermediate 41 is commercially available.
Scheme 10
48 compound of formula is prepared for by synthetic route shown in scheme 11.Intermediate 1 and 44 is commercially available.
Scheme 11
The compound of formula 52 is prepared for by synthetic route shown in scheme 12.Intermediate 49 is commercially available, intermediate 46 show in scheme 11 above.
Scheme 12
Pass through 58 compound of synthetic route preparation formula shown in scheme 13.Intermediate 1 and 53 is commercially available.
Scheme 13
Application method
Formula (I) compound and its pharmaceutically acceptable salt are the selective depressants of DNMT1.These compounds may be used There is the illness of reaction to the selective depression of DNMT1 in treatment.These include but is not limited to before cancer and cancer syndrome and β it is blood red Albumen disease, such as drepanocytosis, herrik syndrome and beta Thalassemia.Therefore, on the other hand, the present invention relates to The method for treating these illnesss.
Suitably, the present invention relates to the method for the treatment of breast cancer, the breast cancer includes inflammatory breast cancer, duct carcinoma and small Leaf cancer.
Suitably, the present invention relates to the methods for the treatment of colon cancer.
Suitably, the present invention relates to the methods for the treatment of cancer of pancreas, including insulinoma, gland cancer, duct adenocarcinoma, glandular scale shape Cancer, acinar cell carcinoma and glucagonoma of pancreas.
Suitably, the present invention relates to the method for the treatment of cutaneum carcinoma, the cutaneum carcinoma includes melanoma, including metastatic melanocyte Tumor.
Suitably, the present invention relates to the methods for the treatment of lung cancer, including Small Cell Lung Cancer, non-small cell lung cancer, squamous cell Cancer, gland cancer and large cell carcinoma.
Suitably, the present invention relates to treatment be selected from following cancer method: lung cancer, osteocarcinoma, cancer of pancreas, cutaneum carcinoma, head cancer, Neck cancer, uterine cancer, oophoroma, gastric cancer, colon cancer, breast cancer, cancer of the esophagus, carcinoma of small intestine, intestinal cancer, internal system cancer, thyroid gland Cancer, parathyroid carcinoma, adrenal, carcinoma of urethra, prostate cancer, carcinoma of penis, carcinoma of testis, carcinoma of ureter, bladder cancer, renal cancer or Liver cancer；The carcinoma of the rectum；The cancer of anal region；Carcinoma of fallopian tube, carcinoma of endometrium, cervix cancer, carcinoma of vagina, carcinoma of vulva, carcinoma of renal pelvis, kidney Cell cancer；Soft tissue sarcoma；Myxoma；Rhabdomyoma；Fibroma；Lipoma；Teratoma；Cholangiocarcinoma；Hepatoblastoma；Blood vessel Sarcoma；Hemangioma；Hepatocellular carcinoma；Fibrosarcoma；Chondrosarcoma；Myeloma；Chronic or acute leukemia；Lymphocyte lymph Tumor；Primary-CNS lymthoma；The tumour of CNS；Spinal column axis tumour；Squamous cell carcinoma；Synovial sarcoma；Malignant pleural mesothelioma； Brain stem glioma；Pituitary adenoma；Bronchial adenoma；Cartilage hamartoma (chondromatous hanlartoma)；Celiothelioma (inesothelioma) and Hodgkin's disease.
Suitably, the present invention relates to the methods that treatment is selected from following disease: the cancer of the brain (glioma), glioblastoma, star Shape cytoma, glioblastoma multiforme, Bannayan-Zonana syndrome, cowden's disease, Lhermitte-Duclos disease, Wilm'stumor, Ewing's sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, head and neck cancer, kidney, liver cancer, melanoma, Oophoroma, cancer of pancreas, gland cancer, duct adenocarcinoma, gland carcinoma squamosum, acinar cell carcinoma, glucagonoma of pancreas, insulinoma, prostate It is cancer, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid cancer, lymphatic T cell leukaemia, chronic myelogenous leukemia, chronic Lymphocytic leukemia, hairy cell leukemia, acute lymphoblastic leukemia, acute myeloid leukaemia, chronic neutrophilic Leukocytic leukemia, acute lymphocytic T cell leukaemia, plasmacytoma, immunoblast mast cell leukemia, jacket cell Leukaemia, Huppert's disease, megakaryoblast leukaemia, Huppert's disease, acute megakaryocytic leukemia, early young grain Cell leukemia, erythroleukemia, malignant lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoblastic T are thin Born of the same parents' lymthoma, Burkitt lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelium cancer, carcinoma of vulva, palace Neck cancer, carcinoma of endometrium, kidney, celiothelioma, cancer of the esophagus, salivary-gland carcinoma, hepatocellular carcinoma, gastric cancer, nasopharyngeal carcinoma, carcinoma of mouth (buccal cancer), mouth cancer (cancer of the mouth), GIST (gastrointestinal stromal tumor), neuroendocrine carcinoma and testis Ball cancer.
Suitably, the present invention relates to the methods of syndrome before the cancer for the treatment of mammal (including people), wherein before the cancer Syndrome is selected from: cervical intraepithelial neoplasia formation, the monoclonal gamma globulin (MGUS) of interrogatory, myeloproliferative disorder are comprehensive It is sign, alpastic anemia, cervical lesions, cutaneous nevus (preceding melanoma), tumour (PIN) (in conduit) in prostatic epithelium, former Position duct carcinoma (DCIS), polyp of colon and serious hepatitis or cirrhosis.
In some embodiments, the compound of the present invention can be used for overcoming T cell tolerance.
In some embodiments, the compound of the present invention can be used for treatment of diabetic nephropathy, diabetes, sertoli cell damage Wound, atherosclerosis, psoriasis, idiopathic pulmonary fibrosis, chorionitis, cirrhosis, rheumatoid arthritis and alzheimer ' Silent disease.
The compounds of this invention can also be used to increasing or enhancing immune response, including increasing the immune response to antigen；Improve It is immune, including improve vaccine potency；And increase inflammation.In some embodiments, the compounds of this invention can be used for enhancing to epidemic disease The immune response of seedling, including but not limited to Listeria vaccine, oncolytic viral vaccine and cancer vaccine, such as GV(tumor cell vaccine of granulocyte-macrophage colony stimutaing factor (GM-CF) gene transfection).
It can include but is not limited to treatment β hemoglobinopathy with the other diseases and illness that the compounds of this invention is treated, such as Drepanocytosis, herrik syndrome and beta Thalassemia disease.
Treatment method of the invention includes having given a effective amount of formula (I) compound or its pharmaceutically acceptable salt to this The patient needed.
The term as used herein " treatment " and its derivative vocabulary, refer to for illness: (1) improving illness or the illness One or more biological manifestations, one or more of (2) interference (a) biological cascade lead to the illness or are responsible for the illness Point or (b) one or more biological manifestations of the illness, (3) mitigate one or more symptoms relevant to the illness or shadow It rings, or (4) slow down the progress of illness or one or more biological manifestations of illness.
Term " treatment " and its derivative vocabulary refer to therapeutic treatment.Treatment therapy be suitable for alleviating symptom or in disease or It is treated under its early symptom being in progress.
It will be appreciated by those skilled in the art that " prevention " is not absolute terms.In medicine, " prevention " is interpreted as referring to prevention Property application drug to significantly reduce illness or biological manifestation a possibility that or seriousness, postpone its occur this illness or its Biological manifestation.
When subject have for example strong cancer family history be perhaps considered to have cancered high risk or when by Examination person, which is exposed to carcinogenic substance or subject and has, suffers from β hemoglobinopathy, such as drepanocytosis, herrik syndrome or β-in When the strong family history of extra large anaemia, prophylactic treatment is suitable.
As used herein, term " effective quantity " and its derivative vocabulary refer to the amount of drug or medicament, will cause for example, grinding Study carefully the biology or medical response of tissue, system, animal or people that personnel or clinician are seeking.In addition, " treatment has term Effect amount " and its derivative vocabulary refer to a certain amount of, and disease, illness or secondary work are caused with the corresponding subject for not receiving the amount compared with The tempo of improved treatment, healing, prevention or alleviation or disease or illness reduces.The term is gone back within its scope Amount including effectively enhancing normal physiological function.
As used herein, " patient " or " subject " refers to people or other mammals.Suitably, patient or subject are People.
Formula (I) compound or its pharmaceutically acceptable salt can be administered by any suitable administration route, including complete Body administration.Formulations for systemic administration includes oral administration and parenteral.Parenteral refers in addition to enteral, transdermal or sucking Administration route, and usually pass through injection or infusion.Parenteral includes intravenous, intramuscular and is subcutaneously injected or is transfused.
Formula (I) compound or its pharmaceutically acceptable salt can with single administration or according to Dosage Regimens Dosage, wherein Multiple dosage are given in given a period of time at various time intervals.For example, dosage can be administered once a day, twice, Three times or four times.It can be with administration dosage until reaching required therapeutic effect or indefinitely maintaining required therapeutic effect.With In the compounds of this invention suitable dosage regimen depend on the compound pharmacokinetic property, such as absorb, distribution and Half-life period can be determined by those skilled in the art.In addition, for the compounds of this invention, suitable dosage regimen, including give The duration of these schemes, depending on treated illness, state of the illness, treated patient age and Physical condition, medical history, the property of concurrent treatment, required therapeutic effect and knowledge and profession in those skilled in the art are known Know the similar factor in range.It will be further understood by those skilled in the art that in view of individual patient to the response of dosage regimen or It changes with time as individual patient needs to change, suitable dosage regimen may need to adjust.
Typical daily dosage can change according to selected specific administration approach.The exemplary dosage ranges of oral administration are Everyone every dose 1mg to 1000mg.Preferred dose for everyone 1-500mg once a day or twice daily.
In addition, formula (I) compound or its pharmaceutically acceptable salt can be used as prodrug administration.As used herein, this hair " prodrug " of bright compound is the functional derivatives of the compound, is finally discharged in vivo after giving patient of the invention Compound.Applying can enable a technician to carry out one or more of as the compounds of this invention of prodrug: (a) change The action of compound in vivo；(b) change the acting duration of compound in vivo；(c) change the fortune of compound in vivo Defeated or distribution；(d) change the solubility of compound in vivo；(e) other difficulties for overcoming the side effect of compound or encountering. The typical functionality derivative for being used to prepare prodrug includes the modification of chemistry or the compound of enzymatic cutting in vivo.These modifications Preparation including phosphate, amide, ether, ester, thioesters, carbonic ester and carbamate.It, can when presence-COOH or-OH group To use pharmaceutically acceptable ester, such as methyl, the ethyl etc. of-COOH, and for acetic acid esters, the maleic acid etc. of-OH, And it is known in the art for changing solubility or the ester of hydrolysis properties.
Therefore, the invention further relates to the prodrugs of formula (I) compound.Suitably, prodrug is dihydrogen phosphate.Suitably, preceding Medicine is 2- amino -3 Methylbutanoic acid ester.
It is included in the prodrug of formula (I):
Biphosphate 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) pyrrolidin-3-yl ester；
Biphosphate 2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) (methyl) amino) ethyl ester；
Biphosphate 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) azetidine -3- base ester；
(2S) -2- amino -3 Methylbutanoic acid 2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- Dicyano -4- ethylpyridine -2- base) piperidin-4-yl) oxygroup) ethyl ester；
Biphosphate 2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) oxygroup) ethyl ester；With
Biphosphate 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) piperidin-4-yl ester；
Its pharmaceutically acceptable salt.
Those skilled in the art are easy to prepare the prodrug of the compounds of this invention.
Formula (I) compound and its pharmaceutically acceptable salt can be known to be used in comprehensive before treating cancer or cancer at least one Other activating agent co-administereds of simulator sickness.
The term as used herein " co-administration " refer to be administered simultaneously or any mode individually sequentially application is as described herein DMNT1 activity inhibitor and be known to be used in treating cancer, including other of chemotherapy and radiotherapy activating agent.Such as this paper institute With term " other activating agents " includes known when to the patient's application for needing treating cancer or shows any of favorable property Compound or therapeutic agent.Preferably, if administration is not administered simultaneously, compound is administered within the time closer to each other.This Outside, whether compound is administered unimportant with identical dosage form, for example, a kind of compound can be another by drug administration by injection Compound can be taken orally.
The following institute of example of other active components (antitumor agent) for combining or being co-administered with the present composition Show.The list is non-limiting.It is expected that other antitumor agents are also used together with the compounds of this invention.
In general, can be co-administered in treatment of cancer of the invention any active to susceptible neoplasm to be treated Antitumor agent.The example of these medicaments can be found in Cancer Principles and Practice of Oncology by V.T.Devita and S.Hellman (editor), the 6th edition (on 2 15th, 2001), Lippincott Williams& Wilkins Publishers.Typical case's antitumor agent for use in the present invention includes but is not limited to anti-micro-pipe agent such as Diterpenes chemical combination Object and vinca alkaloids；Platinum coordination complex；Alkylating reagent such as mustargen, Oxazaphosphorine, alkylsulfonate, Asia Nitrourea and triazenes；Antibiotic formulations, such as anthracycline antibiotic, D actinomycin D and bleomycin；Topoisomerase II inhibits Agent, such as epipodophyllotoxin；Antimetabolite, such as purine and pyrimidine analogue and anti-folic acid compound；Topoisomerase I inhibitor, Such as camptothecine；Hormone and hormone analogs；Signal transduction pathway inhibitor；Nonreceptor tyrosine kinase angiogenesis inhibitors； Immunotherapeutic agent；Promote apoptosis agent；Cell cycle signals transduction inhibitor；Proteasome inhibitor；With cancer metabolic poison.
For being with the combination of the invention together example of combination or the other active components (antitumor agent) being co-administered Chemotherapeutant.
Anti- micro-pipe or antimitotic agent are that have work to the micro-pipe of tumour cell in the M phase of cell cycle or m period The phase specific reagent of property.The example of anti-micro-pipe agent includes but is not limited to diterpene-kind compound and vinca alkaloids.It is derived from Natural diterpene-kind compound is the G in the cell cycle2The phase specific anticancer agents that/M phase works.It is believed that Diterpenes Close the 'beta '-tubulin subunit that object stablizes micro-pipe and in conjunction with the protein.Then the decomposition for inhibiting protein, stops simultaneously Only mitosis and subsequent cell death.The example of diterpene-kind compound includes but is not limited to that taxol and the like is mostly western Taxol.
Taxol, 5 β, 20- epoxy -1,2 α, 4,7 β, 10 β, 13 α-hexahydroxy Japanese yew -11- alkene -9- ketone 4,10- oxalic acid Ester 2- benzoic ether 13- (2R, 3S)-N- benzoyl -3- phenylisoserine ester (5 β, 20-epoxy-1,2 α, 4,7 β, 10 β, 13α-hexa-hydroxytax-11-en-9-one4,10-diacetate 2-benzoate 13-ester with(2R, 3S)-N-benzoyl-3-phenylisoserine)；It is a kind of day separated from Pacific yew tree yewtree Right diterpene product, can be used as injectionIt is commercially available.It is the member of terpene taxane.Taxol is criticized in the U.S. It is mutatis mutandis to treat refractory ovarian and breast cancer in clinical use.
Docetaxel (Docetaxel), 5 β -20- epoxy -1,2 α, 4,7 β, 10 β, 13 α-hexahydroxy Japanese yew -11- alkene -9- Ketone 4- acetic acid esters 2- benzoic ether 13- (2R, 3S)-N- carboxyl -3- phenylisoserine N- tertiary butyl ester, trihydrate, as The solution of injectableIt is commercially available.Docetaxel can be used for treating breast cancer.Docetaxel is appropriate (q.v.) The semi-synthetic derivative of taxol is that the 10- extracted from the needle of European yew tree removes acetyl using natural precursor The preparation of base Baccatine III.The dose-limiting toxicity of docetaxel is neutropenia.
Vinca alkaloids (Vinca alkaloids) are derived from the antitumor of the phase specific of periwinkle plant Drug.Vinca alkaloids work and specifically in conjunction with tubulin in the M phase (mitosis) of cell cycle.Cause This, the tubulin molecule being combined cannot aggregate into micro-pipe.Think that mitosis is stopped in mid-term, subsequent cell death. The example of vinca alkaloids includes but is not limited to vincaleukoblastinum, vincristine and vinorelbine.
Vincaleukoblastinum (Vinblastine), vinblastine sulfate, withInjection is commercially available.Although having shown that It is possible as the second line treatment of various solid tumors, but it initially shows to wrap for treating carcinoma of testis and various lymthomas Include Hodgkin's disease and l&H lymthoma.Bone marrow suppression is the dose-limiting side effect of vincaleukoblastinum.
Vincristine (Vincristine), vincaleukoblastinum 22- oxo-sulfate, withInject solution city It sells.Vincristine is shown for treating acute leukemia, it was found that for treating Huo Qijin and non-Hodgkin's malignant lymphoma.It is de- Hair and effects on neural system are the most common side effects of vincristine, and generate lesser degree of bone marrow suppression and gastrointestinal mucositis work With.
Vinorelbine (Vinorelbine), bis- dehydrogenation -4'- deoxidation-C'- navelbine of 3', 4'- (norvincaleukoblastine) [R- (R*, R*) -2,3- dyhydrobutanedioic acid diester (1:2) (salt)], with vinorelbine wine Stone hydrochlorate injects solutionIt is commercially available, it is semi-synthetic vinca alkaloids.Vinorelbine can be used as individually Drug or combined with other chemotherapeutants (such as cis-platinum), for treating various solid tumors, especially non-small cell lung cancer, evening The prostate cancer of primary breast cancer and hormone refractory.Bone marrow suppression is the most common dose-limiting side effect of vinorelbine.
Platinum coordination complex (Platinum coordination complex) is the anticancer agent of non-phase specific, It interacts with DNA.Platinum complex enters tumour cell, carries out aquation, and with DNA formed inside chain and between friendship Connection, leads to the biological action unfavorable to tumour.The example of platinum coordination complex includes but is not limited to cis-platinum and carboplatin.
Cis-platinum, cis-diammine dichloro close platinum, withIt is commercially available to inject solution.Cis-platinum is used primarily for treatment and turns Shifting property carcinoma of testis and oophoroma and the bladder cancer in advanced stage.The major dose-limiting side effect of cis-platinum is renal toxicity and ear poison Property, the renal toxicity can be controlled by hydration and diuresis.
Carboplatin, diamino [1,1- cyclobutane-dicarboxylic acid radical (2-)-O, O'] close platinum, withIt injects molten Liquid is commercially available.Carboplatin is used primarily for a line and second line treatment for advanced ovarian cancer.Bone marrow suppression is the dose-limiting toxicity of carboplatin.
Alkylating agent is the anticancer drug and strong electrophilic reagent of non-phase specific.In general, alkylating agent is turned by means of alkyl With by nucleophilic moiety such as phosphate (phosphate), amino, sulfydryl, hydroxyl, carboxyl and the imidazole radicals of DNA molecular, with DNA Form covalent bond.This alkylating destroys nucleic acid function, leads to cell death.The example of alkylating agent includes but is not limited to nitrogen Mustard (such as cyclophosphamide, melphalan and Chlorambucil), alkyl sulfonate esters (such as busulfan, nitroso ureas such as Carmustine), with And triazenes (such as Dacarbazine).
Cyclophosphamide (Cyclophosphamide), 2- [bis- (2- chloroethyl) amino] tetrahydro -2H-1,3,2- oxynitride phosphors are miscellaneous Cyclohexadiene 2- oxide monohydrate (2- [bis (2-chloroethyl) amino] tetrahydro-2H-1,3,2- Oxazaphosphorine 2-oxide monohydrate), withIt injects solution or tablet is commercially available.Ring phosphorus Amide can be used as individual drug or with other chemotherapeutic combinations, for treat malignant lymphoma, Huppert's disease and Leukaemia.Alopecia, Nausea and vomiting and leukopenia are the most common dose-limiting side effects of cyclophosphamide.
Melphalan (Melphalan), 4- [bis- (2- chloroethyl) amino]-L- phenylalanine (4- [bis (2- Chloroethyl) amino]-L-phenylalanine), withIt injects solution or tablet is commercially available.Melphalan It can be used for the palliative treatment of Huppert's disease and unresectable epithelial ovarian cancer.Bone marrow suppression is most common dose of melphalan Measure restricted side effect.
Chlorambucil (Chlorambucil), 4- [bis- (2- chloroethyl) amino] benzenebutanoic acid (4- [bis (2- Chloroethyl) amino] benzenebutanoic acid), withTablet is commercially available.Chlorambucil It can be used for chronic lymphocytic leukemia, malignant lymphoma (such as lymphosarcoma, giant follicular lymphoma and Hodgkin's disease) Palliative treatment.Bone marrow suppression is the most common dose-limiting side effect of Chlorambucil.
Busulfan (Busulfan), Busulfan (Isosorbide-5-Nitrae-butanediol Dimethanesulfonate), withTablet is commercially available.Busulfan is used for the aunt of chronic granulocytic leukemia Cease therapy.Bone marrow suppression is the most common dose-limiting side effect of busulfan.
Carmustine (Carmustine), 1,3- [bis- (2- chloroethyl) -1- nitroso ureas (1,3- [bis (2- Chloroethyl) -1-nitrosourea), with Bi-The lyophilized products of single bottle dress are commercially available.Carmustine can be used as list Only drug is combined with other medicines, for appeasing for brain tumor, Huppert's disease, Hodgkin's disease and non-Hodgkin lymphoma Therapy.The bone marrow suppression of delay is the most common dose-limiting side effect of Carmustine.
Dacarbazine (Dacarbazine), 5- (3,3- dimethyl -1- triazenyl)-imidazoles -4- formamide (5- (3,3- Dimethyl-1-triazeno)-imidazole-4-carboxamide), with DTIC-The product of single bottle dress is commercially available. Dacarbazine can be used for the treatment of metastatic malignant melanoma, and can combine with other medicines, the two wires for Hodgkin's disease Treatment.Nausea and vomiting and anorexia are the most common dose-limiting side effects of Dacarbazine.
Antibiotics anticancer agent (Antibiotic anti-neoplastics) is the drug of non-phase specific, knot In conjunction or the intercalation of DNA.In general, this effect leads to stable DNA compound or chain fracture, the normal function of nucleic acid is destroyed, is led Cause cell death.The example of antibiotics anti-tumor drug includes but is not limited to D actinomycin D (such as actinomycin D)；Anthracycline (anthrocyclins) (such as daunorubicin and Doxorubicin)；And bleomycin.
Actinomycin D (Dactinomycin, also referred to as Actinomycin D), withInjection shape Formula is commercially available.Actinomycin D can be used for the treatment of Weir nurse this tumour and rhabdomyosarcoma.Nausea and vomiting and anorexia are actinomyces The plain most common dose-limiting side effect of D.
Daunorubicin (Daunorubicin), (8S- cis- -) -8- acetyl group -10- [(3- amino -2,3, tri- deoxy of 6- α-L- lysol-hexpyranosyl)-oxygroup] -7,8,9,10- tetrahydro -6,8,11- trihydroxy -1- methoxyl group -5,12- aphthacene two Keto hydrochloride, withLiposome injectable forms orInjectable forms city It sells.Daunorubicin can be in the treatment of acute nonlymphocytic leukemia and the relevant Kaposi sarcoma of advanced stage HIV for luring Lead alleviation.Bone marrow suppression is the most common dose-limiting side effect of daunorubicin.
Doxorubicin (Doxorubicin), (8S, 10S) -10- [(3- amino -2,3, tri- deoxidation-α-L- lysol of 6--own pyrrole Mutter glycosyl) oxygroup] -8- glycolyl -7,8,9,10- tetrahydro -6,8,11- trihydroxy -1- methoxyl group -5,12- aphthacene diketone Hydrochloride ((8S, 10S) -10- [(3-amino-2,3,6-trideoxy- α-L-lyxo-hexopyranosyl) oxy] -8- glycoloyl,7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5, 12naphthacenedione hydrochloride), withOr ADRIAMYCINInject solution city It sells.Doxorubicin is mainly used for the treatment of acute lymphoblastic leukemia and acute myeloblastic leukemia, but is also The useful constituent for treating certain solid tumors and lymthoma.Bone marrow suppression is the most common dose-limiting side effect of Doxorubicin.
Bleomycin (Bleomycin) is separated from streptomyces verticillus (streptomyces verticilus) bacterial strain The mixture of cytotoxin glycopeptide antibiotics out, withIt is commercially available.Bleomycin can be used as individually Drug or combined with other medicines, the palliative treatment for squamous cell carcinoma, lymthoma and carcinoma of testis.Lung and dermal toxicity It is the most common dose-limiting side effect of bleomycin.
Topoisomerase II inhibitors include but is not limited to table Podophyllum emodi var chinense lipoxin.
Table Podophyllum emodi var chinense lipoxin (Epipodophyllotoxins) is derived from the phase of mandrake (mandrake) plant The anti-tumor drug of specificity.Table Podophyllum emodi var chinense lipoxin usually by forming ternary complex with topoisomerase II and DNA, causes DNA chain is broken to influence S and G in the cell cycle2The cell of phase.Chain fracture accumulation, then cell death.Table podophyllin poison The example of element includes but is not limited to Etoposide and Teniposide.
Etoposide (Etoposide), 4'- demethyl-table Podophyllum emodi var chinense lipoxin 9 [4,6-0- (R)-ethylidene-β-D- pyrans Glucoside], withIt injects solution or capsule is commercially available, and often referred to as VP-16.Etoposide can be used as list Only drug or with other chemotherapeutic agent combinations, for treating carcinoma of testis and non-small cell lung cancer.Bone marrow suppression be Etoposide most Common side effect.The incidence (incidence) of leukopenia is tended to tighter than the incidence of thrombopenia Weight.
Teniposide (Teniposide), 4'- demethyl-table Podophyllum emodi var chinense lipoxin 9 [4,6-0- (R)-thenylidene-β- D- glucopyranoside], withIt is commercially available to inject solution, and normally referred to as VM-26.Teniposide can be used as Individual drug or with other chemotherapeutic agent combinations, for treating acute leukemia.Bone marrow suppression is that Teniposide is most common Dose-limiting side effect.Teniposide can cause leukopenia and thrombopenia.
Antimetabolic tumour medicine (Antimetabolite neoplasti) is the anti-tumor drug of phase specific, is made For the S phase (DNA synthesis) of cell cycle, by inhibiting the synthesis of DNA, or the synthesis by inhibiting purine or pyrimidine bases And then limit the synthesis of DNA.Therefore, the S phase cannot continue, then cell death.The example of anti-metabolism anti-tumor drug Including but not limited to fluorouracil, methotrexate (MTX), cytarabine, purinethol, thioguanine and gemcitabine (fluorouracil,methotrexate,cytarabine,mecaptopurine,thioguanine,and gemcitabine)。
5 FU 5 fluorouracil, 5- fluoro- 2,4- (1H, 3H) hybar X are commercially available with fluorouracil.The administration of 5 FU 5 fluorouracil is led The inhibition of thymidylic acid synthesis is caused, and is also incorporated into RNA and DNA.It as a result is usually cell death.5 FU 5 fluorouracil can be used as Individual drug or with other chemotherapeutic agent combinations, for treating breast cancer, colon and rectum carcinoma, gastric cancer and cancer of pancreas.Marrow suppression System and catarrh are the dose-limiting side effects of 5 FU 5 fluorouracil.Other fluoropyrimidine analogues include 5- fluorodeoxyuridine One phosphoric acid of nucleosides (floxuridine) and 5- fluorodeoxyuridine.
Cytarabine (Cytarabine), -2 (1H)-pyrimidone (4- of 4- amino -1- β-D- arabinofuranosidase glycosyl Amino-1- β-D-arabinofuranosyl-2 (1H)-pyrimidinone), withIt is commercially available, and lead to Often referred to as Ara-C.Think that cytarabine has cell phase specificity in the S- phase, by the way that cytarabine end to be incorporated into Inhibit the extension of DNA chain in the DNA chain of growth.Cytarabine as individual drug or with other chemotherapeutic agent combinations, be used for Treat acute leukemia.Other cytidine analogs include 5-azacitidine and 2', 2'- difluoro deoxycytidine (gemcitabine). Cytarabine causes leukopenia, thrombopenia and catarrh.
Purinethol, 1,7- dihydro -6H- purine -6- thioketones monohydrate (1,7-dihydro-6H-purine-6- Thione monohydrate), with purineIt is commercially available.Purinethol passes through not yet clear mechanism suppression so far in the S- phase The synthesis of DNA processed has cell phase specificity.Purinethol can be used as individual drug or with other chemotherapeutic agent combinations, be used for Treat acute leukemia.It is expected that bone marrow suppression and gastrointestinal mucositis are the side effects of high dose purinethol.Workable sulfydryl Purine analogue is imuran.
Thioguanine (Thioguanine), 2- amino -1,7- dihydro -6H- purine -6- thioketones (2-amino-1,7- Dihydro-6H-purine-6-thione), withIt is commercially available.Thioguanine passes through not yet clear so far in the S- phase Mechanism inhibit DNA synthesis have cell phase specificity.Thioguanine can be used as individual drug or with other chemotherapeutics Combination, for treating acute leukemia.Bone marrow suppression, including leukopenia, thrombopenia and anaemia are administration sulphur The most common dose-limiting side effect of guanine.However, gastrointestinal side-effect also occurs, and the side effect may be dosage limit Property processed.Other purine analogues include Pentostatin, erythro form hydroxynonyl adenine (erythrohydroxynonyl Adenine), fludarabine phosphate and Cladribine.
Gemcitabine (Gemcitabine), one hydrochloride (β-isomers) of 2'- deoxidation -2', 2'- difluoro cytidine, withIt is commercially available.Gemcitabine is by blocking cell to have cell phase special in the S- phase by the development on the boundary G1/S Property.Gemcitabine can also be used separately for treatment office for treating local advanced Non-small cell lung with cisplatin combination The advanced pancreatic cancer in portion.Bone marrow suppression (including leukopenia, thrombopenia and anaemia) is that gemcitabine is administered most Common dose-limiting side effect.
Methotrexate (MTX), N- [4 [[(2,4- diamino -6- pteridyl) methyl] methylamino] benzoyl]-Pidolidone, It is commercially available with methotrexate sodium.Methotrexate (MTX) has cell phase specific effect in the S- phase, by inhibiting purine biosynthesis nucleosides Acid inhibits the synthesis, reparation and/or duplication of DNA with dehydrofolic acid reductase needed for thymidylic acid.Methotrexate (MTX) can be used as list Only drug or with other chemotherapeutic agent combinations, for treating choriocarcinoma, meningeal leukemia, non-Hodgkin lymphoma, and cream Gland cancer, head cancer, neck cancer, oophoroma and bladder cancer.It is expected that bone marrow suppression (leukopenia, thrombopenia and anaemia) and Catarrh is that the side effect of methotrexate (MTX) is administered.
Camptothecine (Camptothecins), including camptothecine and camptothecin derivative can be used as topoisomerase I suppression Preparation comes using or develops.Think that camptothecine cytotoxic activity is related to its topoisomerase I inhibitory activity.The reality of camptothecine Example includes but is not limited to Irinotecan, Hycamtin and following 7- (4- methyl piperazine base-the methylene)-Asia 10,11- second two The various optically active forms of oxygroup -20-camptothecin.
Irinotecan hydrochloride (Irinotecan HCl), (4S) -4,11- diethyl -4- hydroxyl -9- [(4- piperidino piperazine Pyridine subbase) carbonyl oxygroup] -1H- pyrans simultaneously [3', 4', 6,7] indolizino [1,2-b] quinoline -3,14 (4H, 12H)-diketone Hydrochlorate, withIt is commercially available to inject solution.
Irinotecan (Irinotecan) is the derivative of camptothecine, is incorporated in together with its active metabolite SN-38 On topoisomerase I-DNA compound.Think that (irreparable) due to double-strand unrepairable is broken, and leads to cell occur Toxicity, the fracture is by topoisomerase I: DNA: mutual between Irinotecan or SN-38 ternary complex and replicase Caused by effect.Irinotecan can be used for treating the metastatic carcinoma of colon or rectum.The dose-limiting secondary work of irinotecan hydrochloride With being bone marrow suppression, including neutropenia, and the GI effect including diarrhea.
Hydrochloric acid Hycamtin (Topotecan HCl), (S) -10- [(dimethylamino) methyl] -4- ethyl -4,9- dihydroxy Base -1H- pyrans simultaneously [3', 4', 6,7] indolizino [1,2-b] quinoline -3,14- (4H, 12H)-one hydrochloride of diketone ((S) -10- [(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3’,4’,6,7]indolizino [1,2-b] quinoline-3,14- (4H, 12H)-dione monohydrochloride), withInjection Solution is commercially available.Hycamtin is the derivative of camptothecine, in conjunction with topoisomerase I-DNA compound, and is prevented single-stranded disconnected The reconnection split, the single-strand break are torsional tension (torsional strain) institutes of topoisomerase I response DNA molecular It is caused.Hycamtin is used for the second line treatment of Metastatic Tumor of Ovaray and Small Cell Lung Cancer.Hydrochloric acid Hycamtin it is dose-limiting Side effect is bone marrow suppression, mainly neutropenia.
Equally interestingly below formula A camptothecin derivative, including racemic mixture (R, S) form with And R and S enantiomer:
Chemical name is " 7- (4- methylpiperazino-methylene) -10,11- ethylenedioxy -20 (R, S)-camptothecine (racemic mixture) or " 7- (4- methylpiperazino-methylene) -10,11- ethylenedioxy -20 (R)-(R pairs of camptothecine Reflect body) or " 7- (4- methylpiperazino-methylene) -10,11- ethylenedioxy -20 (S)-camptothecine (S enantiomer).In beauty State's patent 6,063,923；5,342,947；5,559,235；With 5,491,237 in describe this compound and related compounds Object, including preparation method.
Hormone and hormone analogs are the compounds useful to treatment of cancer, and wherein hormone is given birth to growth of cancers and/or not There is relationship between length.The example of hormone and hormone analogs use for cancer treatment includes but is not limited to: adrenal cortex class is solid Alcohols, such as prednisone and prednisolone, have for treating malignant lymphoma and acute leukemia；Aminoglutethimide and its His aromatase inhibitor, such as Anastrozole, Letrozole, R 83842 (vorazole) and Exemestane, have for treating kidney The breast cancer (being related to estrogen receptor) of upper gland cortical carcinoma and hormone dependant；Progesterone (progeserins), for example, acetic acid first it is pregnant Ketone is used to treat the breast cancer and carcinoma of endometrium of hormone dependant；Estrogen, androgen and antiandrogen drug, such as fluorine Ta meter Te, Nilutamide, Bicalutamide, cyproterone acetate；With 5α-reductase such as Finasteride and dutasteride, have For treating prostate cancer and benign prostatauxe；Antiestrogen, for example, tamoxifen, Toremifene, Raloxifene, Selectivity disclosed in Droloxifene, Idoxifene and U.S. Patent number 5,681,835,5,877,219 and 6,207,716 Estrogenic agents (SERMS), these substances are used to treat the breast cancer and other neurological susceptibility cancers of hormone dependant；And rush Gonadotropin releasing hormone (GnRH) and the like stimulates luteinizing principle (LH) and/or follicle-stimulating hormone (FSH) (FSH) Release, for treating prostate cancer, this substance is such as LHRH agonist and antagonist, such as goserelin acetate and bright Third Rayleigh.
Signal transduction path inhibitor is such inhibitor, blocks or inhibits to cause the chemical mistake changed into the cell Journey.This variation as described herein is cell Proliferation or differentiation.It include receptor junket ammonia for signal transduction inhibitor of the invention Acid kinase inhibitor, nonreceptor tyrosine kinase inhibitor, SH2/SH3 structural domain blocking agent, serine/threonine kinase inhibit Agent, phosphatidylinositol 3-kinase inhibitor, Myo-Inositol signal transduction inhibitor and Ras oncogene inhibitor.
Several protein tyrosine kinase catalysis participate in the specific tyrosinyl residues in the multiple proteins of cell cycle regulation Phosphorylation.The protein tyrosine kinase can broadly be divided into receptor kinase or non-receptor kinase.
Receptor tyrosine kinase is with extracellular ligand binding structural domain, transmembrane domain and tyrosine kinase domain Transmembrane protein.Receptor tyrosine kinase participates in the adjusting of cell growth, and commonly referred to as growth factor receptors.It is many these Kinases for example by the unsuitable activation that is overexpressed or is mutated or uncontrolled activation (i.e. abnormal kinase growth factor by Body activity) it has been demonstrated that uncontrolled cell is caused to grow.Therefore, the abnormal activity of the kinases grows with malignant tissue and has It closes.Therefore, the inhibitor of the kinases can provide cancer treatment method.Growth factor receptors include such as epidermal growth factor receptor Body (EGFr), growth factor receptors (PDGFr), erbB2, erbB4, vascular endothelial growth factor receptor from blood platelet (VEGFr), tyrosine kinase (TIE-2, tyrosine with immunoglobulin-like and epidermal growth factor homeodomain kinase with immunoglobulin-like and epidermal growth factor homology Domains), insulin-like growth factor-I (IGFI) receptor, macrophage colony stimulating factor (cfms), BTK, ckit, cmet, Fibroblast growth factor (FGF) receptor, Trk receptor (TrkA, TrkB and TrkC), ephrins (eph) receptor and RET are former Oncogene.Several inhibitor of growth receptors just in exploitation, including ligand antagonists, antibody, tyrosine kinase inhibitor and Antisense oligonucleotides.The drug of growth factor receptors and inhibition growth factor receptor function is disclosed in such as following documents: Kath,John C.,Exp.Opin.Ther.Patents(2000)10(6):803-818；Shawver etc., DDT, volume 2 the 2nd Phase, 2 months 1997；And Lofts, F.J. etc., " Growth factor receptors as targets ", New Molecular Targets for Cancer Chemotherapy, ed.Workman, Paul and Kerr, David, CRC press 1994,London.
Suitably, pharmaceutical active compounds of the invention are applied in combination with VEGFR inhibitor, suitably VEGFR inhibitor For 5- [[4- [(2,3- dimethyl -2H- indazole -6- base) methylamino] -2- pyrimidine radicals] amino] -2- methyl benzenesulfonamide, or Its pharmaceutically acceptable salt is suitably its mono-hydrochloric salts, discloses and want in international application no PCT/US01/49367 Ask protection, international filing date is 19 days, international publication number WO02/059110 December in 2001, and the International Publication date is On August 1st, 2002, the entire disclosure is hereby incorporated by reference, and be embodiment 69 compound 5- [[4- [(2, 3- dimethyl -2H- indazole -6- base) methylamino] -2- pyrimidine radicals] amino] -2- methyl benzenesulfonamide can be by international application no It is prepared described in PCT/US01/49367.
Suitably, 5- [[4- [(2,3- dimethyl -2H- indazole -6- base) methylamino] -2- pyrimidine radicals] amino] -2- first Base benzsulfamide is the form of mono-hydrochloric salts.The salt form can be by those skilled in the art according to international application no PCT/US01/ Description preparation in 49367, international filing date are on December 19th, 2001.
5- [[4- [(2,3- dimethyl -2H- indazole -6- base) methylamino] -2- pyrimidine radicals] amino] -2- Methyl benzenesulfonyl Amine is commercially available as mono-hydrochloric salts, and general entitled pazopanib, trade name
Pazopanib is related to cancer and the treatment of eye disease/angiogenesis.Suitably, the present invention relates to cancers and eye The treatment of disease/angiogenesis, is suitably related to age-dependent macular degeneration, this method include individually or with pazopanib group Close application formula (I) compound.
The tyrosine kinase for being not belonging to growth factor receptor kinase is referred to as nonreceptor tyrosine kinase.For in the present invention As the target of anticancer drug or the nonreceptor tyrosine kinase of potential target include cSrc, Lck, Fyn, Yes, Jak, CAbl, FAK (focal adhesion kinase), bruton's tyrosine kinase (Brutons tyrosine kinase) and Bcr-Abl.It is described Non- receptor kinase and the drug of inhibition nonreceptor tyrosine kinase function are described in following documents: Sinh, S. and Corey, S.J.,(1999)Journal of Hematotherapy and Stem Cell Research 8(5):465–80；With Bolen,J.B.,Brugge,J.S.,(1997)Annual review of Immunology.15:371-404。
SH2/SH3 structural domain blocking agent is the medicine for destroying SH2 or SH3 structural domain in a variety of enzymes or adaptin and combining Object, the enzyme or adaptin include PI3-Kp85 subunit, Src family kinase, adapter molecule (Shc, Crk, Nck, Grb2) And Ras-GAP.SH2/SH3 structural domain as anticancer drug target has been discussed in the following documents: Smithgall, T.E. (1995), Journal of Pharmacological and Toxicological Methods.34 (3) 125-32.
Serine/threonine kinase inhibitor includes map kinase cascade blocking agent comprising Raf kinases (rafk) blocks Agent, mitogen or extracellular regulated kinases (MEK) blocking agent and extracellular regulated kinases (ERKs) blocking agent；And protein kinase C family member's blocking agent, including PKC blocking agent (PKC- α, β, γ, ε, μ, λ, ι, ζ blocking agent), IkB kinase families (IKKa, IKKb) blocking agent, PKB family kinase blocking agent, akt kinase families member's blocking agent, PDK1 and TGF-β receptor kinase block Agent.The serine/threonine kinase and its inhibitor are described in following documents: Yamamoto, T., Taya, S., Kaibuchi,K.,(1999),Journal of Biochemistry.126(5)799-803；Brodt, P, Samani, A. and Navab,R.(2000),Biochemical Pharmacology,60.1101-1107；Massague,J.,Weis-Garcia, F.(1996)Cancer Surveys.27:41-64；Philip, P.A. and Harris, A.L. (1995), Cancer The Bioorganic and Medicinal such as Treatment and Research.78:3-27, Lackey, K. Chemistry Letters,(10),2000,223-226；U.S. Patent number 6,268,391；The Nature such as Pearce, L.R Reviews Molecular Cell Biology (2010) 11,9-22 and Martinez-Iacaci, L. etc., Int.J.Cancer (2000), 88(1),44-52。
Suitably, pharmaceutical active compounds of the invention are applied in combination with mek inhibitor.Suitably, N- { 3- [3- cyclopropyl Base -5- (the iodo- phenyl amino of the fluoro- 4- of 2-) -6,8- dimethyl -2,4,7- trioxy- -3,4,6,7- tetrahydro -2H- pyrido [4,3- D] pyrimidine -1- base] phenyl acetamide or its pharmaceutically acceptable salt or solvate, suitably its dimethyl sulfoxide it is molten Object is closed in agent, and protection is disclosed and claimed in international application no PCT/JP2005/011082, and international filing date is in June, 2005 10 days；International publication number is WO 2005/121142 and international publication day is on December 22nd, 2005, and the entire disclosure is logical Reference is crossed to be incorporated herein in.N- { 3- [3- cyclopropyl -5- (the iodo- phenyl amino of the fluoro- 4- of 2-) -6,8- dimethyl -2,4,7- three Oxo -3,4,6,7- tetrahydro -2H- pyrido [4,3-d] pyrimidine -1- base] phenyl } acetamide can be as open such as on January 19th, 2006 U.S. Patent Publication No. US 2006/0014768 described in prepare, the entire disclosure is hereby incorporated by reference.
Suitably, pharmaceutical active compounds of the invention are applied in combination with B-Raf inhibitor.Suitably, N- { 3- [5- (2- Amino -4- pyrimidine radicals) -2- (1,1- dimethyl ethyl) -1,3- thiazole-4-yl] -2- fluorophenyl -2,6- difluorobenzenesulfonamide or Its pharmaceutically acceptable salt discloses and claims protection, international application in international application no PCT/US2009/042682 Day is on May 4th, 2009, and the entire disclosure is incorporated herein by reference.N- { 3- [5- (2- amino -4- pyrimidine Base) -2- (1,1- dimethyl ethyl) -1,3- thiazole-4-yl] -2- fluorophenyl } -2,6- difluorobenzenesulfonamide can be such as international Shen It please be prepared described in number PCT/US2009/042682.
Suitably, pharmaceutical active compounds of the invention are applied in combination with Akt inhibitor.Suitably, N- { (1S) -2- ammonia Base -1- [(3,4- difluorophenyl) methyl] ethyl } the chloro- 4- of -5- (the chloro- 1- methyl-1 H- pyrazoles -5- base of 4-)) -2- furoyl Amine or its pharmaceutically acceptable salt, disclose and claim in international application no PCT/US2008/053269, international The applying date is on 2 7th, 2008；International publication number is WO 2008/098104 and International Publication day is on August 14th, 2008, Complete disclosure is incorporated herein by reference.N- { (1S) -2- amino -1- [(3,4- difluorophenyl) methyl] ethyl } - The chloro- 4- of 5- (the chloro- 1- methyl-1 H- pyrazoles -5- base of 4-) -2- furoylamide is the compound of embodiment 224, and can be as It is prepared described in international application no PCT/US2008/053269.
Suitably, pharmaceutical active compounds of the invention are applied in combination with Akt inhibitor.Suitably, N- { (1S) -2- ammonia Base -1- [(3- fluorophenyl) methyl] ethyl } the chloro- 4- of -5- (the chloro- 1- methyl-1 H- pyrazoles -5- base of 4-) -2- thenoyl amine or its Pharmaceutically acceptable salt discloses and claims protection, international filing date in international application no PCT/US2008/053269 It is on 2 7th, 2008；International publication number is WO 2008/098104 and International Publication day is on August 14th, 2008, all public It is incorporated herein by reference to open content.N- { (1S) -2- amino -1- [(3- fluorophenyl) methyl] ethyl } chloro- 4- (4- of -5- Chloro- 1- methyl-1 H- pyrazoles -5- base) -2- thenoyl amine be embodiment 96 compound, and can be such as international application no It is prepared described in PCT/US2008/053269.Suitably, N- { (1S) -2- amino -1- [(3- fluorophenyl) methyl] ethyl } -5- Chloro- 4- (the chloro- 1- methyl-1 H- pyrazoles -5- base of 4-) -2- thenoyl amine is the form of hydrochloride.Salt form can be by this field skill Art personnel prepare according to the description in international application no PCT/US2010/022323, and international filing date is January 28 in 2010 Day.
The inhibitor of -3 family member of phosphatidylinositols includes the blocking agent of PI3- kinases, ATM, DNA-PK and Ku, they It can be also used in the present invention.The kinases discusses in the following documents: Abraham, R.T. (1996), Current Opinion in Immunology.8(3)412-8；Canman,C.E.,Lim,D.S.(1998),Oncogene 17(25)3301-3308； Jackson,S.P.(1997),International Journal of Biochemistry and Cell Biology.29 (7):935-8；And Zhong, H. etc., Cancer res, (2000) 60 (6), 1541-1545.
The present invention is also concerned with muscle-inositol signal transduction inhibitor, and such as phospholipase C blocking agent is similar with inositol Object.The signal transduction inhibitor is described in the following documents: Powis, G. and Kozikowski A., (1994) New Molecular Targets for Cancer Chemotherapy ed., Paul Workman and David Kerr, CRC press 1994,London。
Another group of signal transduction path inhibitor is Ras oncogene inhibitor.The inhibitor includes following substances Inhibitor: farnesyl transferase, geranyl-geranyl transferase and CAAX protease and antisense oligonucleotides, ribozyme and exempt from Epidemic disease treatment.The inhibitor is proven and blocks ras activation in the cell containing wild-type mutant ras, therefore conduct Antiproliferative.Ras oncogene inhibitor discusses in the following references: Scharovsky, O.G., Rozados, V.R., Gervasoni,S.I.Matar,P.(2000),Journal of Biomedical Science.7(4)292-8；Ashby, M.N.(1998),Current Opinion in Lipidology.9(2)99–102；And BioChim.Biophys.Acta, (19899)1423(3):19-30。
As mentioned above, signal transduction inhibitor is also used as the antibody antagonists of receptor kinase ligand binding.Group letter Number pathway inhibitor includes purposes of the humanized antibody for the extracellular ligand binding domain of receptor tyrosine kinase.Such as Imclone C225EGFR specific antibody is (referring to Green, M.C. etc., Monoclonal Antibody Therapy for Solid Tumors,Cancer Treat.Rev.,(2000),26(4),269-286)；ErbB2 antibody (ginseng See Tyrosine Kinase Signalling in Breast cancer:erbB Family Receptor Tyrosine Kinases,Breast cancer Res.,2000,2(3),176-183)；And 2CB VEGFR2 specific antibody (referring to Brekken, R.A. etc., Selective Inhibition of VEGFR2Activity by a monoclonal Anti- VEGF antibody blocks tumor growth in mice,Cancer Res.(2000)60,5117-5124)。
Non- receptor kinase angiogenesis inhibitors can also be used for the present invention.Above for signal transduction inhibitor (two kinds by Body is receptor tyrosine kinase) discuss the inhibitor of angiogenesis relevant VEGFR and TIE2.Angiogenesis usually with ErbB2/EGFR signal transduction is related, because the inhibitor that erbB2 and EGFR has been displayed inhibits angiogenesis, mainly VEGF table It reaches.Therefore, nonreceptor tyrosine kinase inhibitor can be applied in combination with the compounds of this invention.For example, anti-VEGF antibody, no It identifies VEGFR (receptor tyrosine kinase), but and ligand binding；Integrin (alphav beta3) micromolecular inhibitor, can press down Angiogenesis processed；Also susceptible of proof and disclosed compound combination use for Endostatin and angiostatin (non-RTK).(See Bruns CJ etc. (2000), Cancer Res., 60:2926-2935；Schreiber AB, Winkler ME and Derynck R. (1986), Science, 232:1250-1253；Yen L etc. (2000), Oncogene 19:3460-3469).
Medicament for Immunotherapy regimens can also be used with formula (I) compound combination.It can be with there are many immunization strategy Generate immune response.These strategies are usually in tumor vaccination field.Combined by using micromolecular inhibitor and inhibits signal Pathway, the effect of immunological method can be greatly enhanced.About immune/tumor vaccine method for erbB2/EGFR Discussion can be found in Reilly RT etc. (2000), Cancer Res.60:3569-3576.
Medicament (for example, bcl-2 antisense oligonucleotides) for promoting apoptosis scheme can be used in combination of the invention. Bcl-2 protein family member blocks Apoptosis.Therefore, the up-regulation of bcl-2 is related with chemoresistance.Studies have shown that epidermis is raw The anti-apoptotic members (that is, mcl-1) of the long factor (EGF) stimulation bcl-2 family.Accordingly, it is intended to lower bcl-2 table in tumour The strategy reached is verified to have clinical benefit, and is now arranged in during the II/III phase tests, i.e. the G3139bcl-2 of Genta is anti- Oligonucleotide.In Water JS etc. (2000), discussed in J.Clin.Oncol.18:1812-1823 using for bcl-2 Antisense oligonucleotides strategy this rush apoptosis strategy.
Cell cycle signals conduction depressant drug inhibits to participate in the molecule of cell cycle control.Referred to as cyclin relies on Property the kinases protein kinase family of (CDKs) and its logical with the interactions of the protein families of referred to as cyclin control Cross the progress of eukaryotic cell cycle.Different cyclins/CDK compound coordination activation and inactivation are for the cell cycle Normal progression is required.Various kinds of cell periodic signal conduction depressant drug is just in exploitation.For example, cyclin dependant The example of kinases (including CDK2, CDK4 and CDK6) and its inhibitor is described in such as Rosania, Exp.Opin.Ther.Patents (2000) 10 (2): 215-230.In addition, p21WAF1/CIP1 has been described as the cell cycle Protein dependent kinase (Cdk) effective and extensive inhibitor (Ball etc., Progress in Cell Cycle Res., 3: 125(1997)).The compound of known induction p21WAF1/CIP1 expression involves the inhibition of cell Proliferation and shows tumour suppression Active (Richon etc., Proc.Nat Acad.Sci.U.S.A.97 (18): 10014-10019 (2000)) is made, and as cell Periodic signal conduction depressant drug is included.Histon deacetylase (HDAC) (HDAC) inhibitor is related to the transcription of p21WAF1/CIP1 It activates (Vigushin etc., Anticancer Drugs, 13 (1): 1-13 (in January, 2002)), and is the suitable cell cycle Signal transduction inhibitor for being applied in combination herein.
The example of this hdac inhibitor includes:
1. Vorinostat, including its pharmaceutically acceptable salt.Marks etc., Nature Biotechnology 25, 84to 90(2007)；Stenger, Community Oncology 4,384-386 (2007).
Vorinostat has chemical structure below and title:
N- hydroxy-n '-phenyl-suberamide
2. romidepsin, including its pharmaceutically acceptable salt.
Vinodhkumar etc., Biomedicine&Pharmacotherapy 62 (2008) 85-93.
Romidepsin has chemical structure below and title:
(propyl- 2- the yl) -2- oxa- -12,13- of (1S, 4S, 7Z, 10S, 16E, 21R) -7- ethylidene -4,21- two dithia - Tetra- azabicyclo of 5,8,20,23- [8.7.6], 23 carbon -16- alkene -3,6,9,19,22- pentone
3. pabishta, including its pharmaceutically acceptable salt.Drugs of the Future 32 (4): 315-322 (2007).
Pabishta has chemical structure below and title:
(2E)-N- hydroxyl -3- [4- ({ [2- (2- Methyl-1H-indole -3- base) ethyl] amino } methyl) phenyl] acryloyl Amine
4. valproic acid, including its pharmaceutically acceptable salt.Gottlicher, et al., EMBO be J.20 (24): 6969- 6978(2001)。
Valproic acid has chemical structure below and title:
Valproic acid
5.Mocetinostat (MGCD0103), including its pharmaceutically acceptable salt.Balasubramanian etc., Cancer Letters 280:211-221 (2009).
Mocetinostat has chemical structure below and title:
N- (2- aminophenyl) -4- [[(4- pyridin-3-yl pyrimidine -2-base) amino] methyl] benzamide
Other examples of such hdac inhibitor are included in Bertrand European Journal of Medicinal In Chemistry 45, (2010) 2095-2116, especially wherein the compound of table 3 is as follows.
Proteasome inhibitor is the drug of blocks protein enzyme body effect, and the proteasome is the cell of decomposing protein Compound, such as p53 albumen.Multiple protein enzyme body inhibitor has been listed or has been studied for treating cancer.For combining herein Suitable proteasome inhibitor include:
1. bortezomibIncluding its pharmaceutically acceptable salt.Adams J, Kauffman M (2004), Cancer Invest 22 (2): 304-11.
Bortezomib has chemical structure below and title.
[(1R)-3- methyl-1-({ (2S)-3- phenyl-2- [(pyrazine-2- base carbonyl) amino] propiono } amino) butyl] Boric acid
2.Disulfiram, including its pharmaceutically acceptable salt.
Bouma etc., (1998) .J.Antimicrob.Chemother.42 (6): 817-20.
Disulfiram has chemical structure below and title.
1,1', 1 ", 1 " '-[disulphanes diyl is bis- (thiocarbonyl group nitrilo-)] four ethane
3. Epigallo-catechin gallate (EGCG) (EGCG), including its pharmaceutically acceptable salt.Williamson etc., (in December, 2006), The Journal of Allergy and Clinical Immunology 118 (6): 1369-74.
Epigallo-catechin gallate (EGCG) has chemical structure below and title.
[(2R, 3R) -5,7- dihydroxy -2- (3,4,5- trihydroxy phenyl) chroman -3- base] 3,4,5-trihydroxy benzoic acid Ester
4.Salinosporamide A, including its pharmaceutically acceptable salt.Feling etc., (2003), Angew.Chem.Int.Ed.Engl.42 (3): 355-7.
Salinosporamide A has chemical structure below and title.
(4R, 5S) -4- (2- chloroethyl) -1- ((1S)-hexamethylene -2- alkenyl (hydroxyl) methyl) -5- methyl -6- oxa- -2- Azabicyclo [3.2.0] heptane -3,7- diketone
5. Carfilzomib, including its pharmaceutically acceptable salt.Kuhn DJ etc., Blood, 2007,110:3281-3290.
Carfilzomib has chemical structure below and title.
(S)-4- methyl-N- ((S)-1- (((S)-4- methyl-1-((R)-2- methyl oxirane-2- base)-1- oxo Amyl- 2- yl) amino) -1- oxo -3- phenyl propyl- 2- yl) -2- ((S) -2- (2- morpholino acetylamino) -4- phenyl butyramide Base) pentanamide
70 kilodalton heat shock proteins (Hsp70) and 90 kilodalton heat shock proteins (Hsp90) are generally expressed The family of heat shock protein.Hsp70s and Hsp90s is over-expressed in certain cancer types.Studying some Hsp70s and Hsp90s inhibitor carrys out treating cancer.Suitable Hsp70s and Hsp90s inhibitor is applied in combination herein comprising:
1.17-AAG (geldanamycin), including its pharmaceutically acceptable salt.Jia W etc., Blood.2003Sep 1； 102 (5): 1824-32.
17-AAG (geldanamycin) has chemical structure below and title.
17- (allyl amino) -17-AAG
2. radicicol, including its pharmaceutically acceptable salt.(Lee etc., Mol Cell Endocrinol.2002, 188,47-54)
Radicicol has chemical structure below and title.
The chloro- 9,11- dihydroxy -14- methyl-15 of (1aR, 2Z, 4E, 14R, 15aR) -8-, 15a- dihydro -1aH- benzo [c] Oxireme simultaneously -6,12 (7H, 14H)-diketone of [2,3-k] [1] oxa- ring tetradecene
Cancer metabolic poison-many tumour cells are shown and the visibly different metabolism of normal tissue.For example, glycolysis Rate (metabolic process for converting glucose into pyruvic acid) increase, and generate pyruvic acid be reduced to lactic acid, without It is to circulate in mitochondria further to aoxidize by tricarboxylic acids (TCA).This effect is frequently observed under aerobic conditions It answers, and referred to as Warburg effect.
Lactate dehydrogenase A (LDH-A) is the isotype for the lactic dehydrogenase expressed in muscle cell, by by pyruvic acid also Then original can output it cell at lactate, play a crucial role in tumour cell metabolism.The enzyme has been demonstrated in many It is raised in tumor type.The change of glucose metabolism described in Warburg effect is for the growth of cancer cell and proliferation It is vital, and have shown that striking low LDH-A using RNA-i leads to cell Proliferation and tumour growth in heteroplastic transplantation model Reduction.
D.A.Tennant etc., Nature Reviews, 2010,267.
P.Leder etc., Cancer Cell, 2006,9,425.
High-caliber fatty acid synthase (FAS) has been had found in cancer precursors lesion.The pharmacology of FAS inhibits to influence The expression of crucial oncogene involved in cancer development and maintenance.Alli et al., Oncogene (2005) 24,39-46.doi: 10.1038。
Cancer metabolic poison, including LDH-A inhibitor and fatty acid biological synthetic inhibitor (or FAS inhibitor) are fitted Conjunction is used in combination with the compounds of this invention.
For being combined with CD73 inhibiting compound of the invention or another or a variety of active ingredients of co-administered Other examples of (antitumor agent) are anti-PD-L1 agent.
Anti- PD-L1 antibody and preparation method thereof is known in the art.
This antibody for PD-L1 can be it is polyclonal or monoclonal, and/or recombination and/or humanization 's.
Illustrative PD-L1 antibody is disclosed in:
United States Patent (USP) 8,217,149；12/633,339；
United States Patent (USP) 8,383,796；13/091,936；
United States Patent (USP) 8,552,154；13/120,406；
U.S. Patent application 20110280877；13/068337；
U.S. Patent application 20130309250；13/892671；
WO2013019906；
WO2013079174；
US application 13/511,538 (is submitted) on August 7th, 2012, is the U.S. of international application no PCT/US10/58007 Thenational phase (is submitted) for 2010；
With
US application 13/478,511 (submission on May 23rd, 2012).
The other exemplary antibodies (also referred to as CD274 or B7-H1) and application method of PD-L1 are disclosed in U.S. Patent number 7,943,743；US20130034559, WO2014055897, United States Patent (USP) 8,168,179；With U.S. Patent number 7,595,048. PD-L1 antibody as treating cancer immunomodulator just in exploitation.
It in one embodiment, is antibody disclosed in U.S. Patent number 8,217,149 for the antibody of PD-L1.? In another embodiment, anti-PD-L1 antibody includes the CDR of antibody disclosed in U.S. Patent number 8,217,149.
It in another embodiment, is antibody disclosed in U.S. Application No. 13/511,538 for the antibody of PD-L1. In another embodiment, anti-PD-L1 antibody includes the CDR of antibody disclosed in U.S. Application No. 13/511,538.
In another embodiment, the antibody of PD-L1 is antibody disclosed in application number 13/478,511.At another In embodiment, anti-PD-L1 antibody includes the CDR of antibody disclosed in U.S. Application No. 13/478,511.
In one embodiment, anti-PD-L1 antibody is BMS-936559 (MDX-1105).In another embodiment In, anti-PD-L1 antibody is MPDL3280A (RG7446).In another embodiment, anti-PD-L1 antibody is MEDI4736.
Another or a variety of active ingredients for combining or being co-administered with CD73 inhibiting compound of the invention Other examples of (antitumor agent) are PD-1 antagonists.
" PD-1 antagonist " refer to block the PD-L1 that is expressed on cancer cell with immunocyte (T cell, B cell or NKT cell) on the PD-1 that the expresses any compound or biomolecule that combine, and preferably also block and expressed on cancer cell The combination of PD-L2 and the PD-1 of immunocyte expression.The substitution title or synonym of PD-1 and its ligand include: for PD-1's PDCD1, PD1, CD279 and SLEB2；For PDCD1L1, PDL1, B7H1, B7-4, CD274 and B7-H of PD-L1；For PD- PDCD1L2, PDL2, B7-DC, Btdc and CD273 of L2.In terms of the wherein present invention of human individual to be treated or embodiment Any embodiment in, the combination of PD-1 Antagonist block human PD-L 1 and people PD-1, and preferably block human PD-L 1 and PD- The combination of L2 and people PD-1.People PD-1 amino acid sequence can be numbered in NCBI locus: be found in NP_005009.Human PD-L 1 It can number in NCBI locus with PD-L2 amino acid sequence: be found in NP_054862 and NP_079515 respectively.
The PD-1 antagonist that can be used for any aspect of the present invention includes monoclonal antibody (mAb) or its antigen-binding fragment, It specifically binds PD-1 or PD-L1, and preferably specifically binds people PD-1 or human PD-L 1.MAb can be human antibody, people Source antibody or chimeric antibody, and may include human constant region.In some embodiments, the human constant region is selected from IgG1, IgG2, IgG3 and IgG4 constant region, and in preferred embodiments, human constant region is IgG1 or IgG4 constant region. In some embodiments, antigen-binding fragment is selected from Fab, Fab'-SH, F (ab') 2, scFv and Fv segment.
It is described in conjunction with the example of people PD-1 and the mAb of various aspects for use in the present invention and embodiment US7488802、US7521051、US8008449、US8354509、US8168757、WO2004/004771、WO2004/ 072286, WO2004/056875 and US2011/0271358.
The specific anti-human PD-1mAb for being used as PD-1 antagonist in any aspect of the invention and embodiment includes: MK-3475, have WHO Drug Information, Vol.27, the 2nd phase, structure described in the 161-162 pages (2013) Humanization IgG4mAb and it includes heavy chain shown in Fig. 6 and light-chain amino acid sequences；Receive Wu Dankang, a kind of human IgG 4 is single Clonal antibody has structure described in 68-69 pages of WHO Drug Information, Vol.27, No.1, the (2013), Include heavy chain shown in fig. 7 and light-chain amino acid sequence；Humanized antibody h409A11, h409A16 and h409A17, description In WO2008/156712 and AMP-514, developed by Medimmune.
Other PD-1 antagonists that can be used for any aspect of the present invention and embodiment include specifically binding exempting from for PD-1 Epidemic disease adhesin, and people PD-1, such as a kind of fusion protein are preferably specifically bound, contain the extracellular of PD-1 or PD-L2 Or the bound fraction of PD-L1, the area Fc with constant domain, such as immunoglobulin molecules.In WO2010/027827 and The example of the immunoadhesin molecule of specific binding PD-1 is described in WO2011/066342.In treatment method of the invention, medicine Object and on the way be used as PD-1 antagonist specific fusion protein include AMP-224 (also referred to as B7-DCIg), be PD-L2- FC fusion protein and in conjunction with people PD.
It is described in conjunction with other examples of human PD-L 1 and the mAb for the treatment of method for use in the present invention, drug and purposes In WO2013/019906, WO2010/077634A1 and US8383796.In treatment method of the invention, drug and with using on the way Make PD-1 antagonist specific anti-human PD-L1mAb include MPDL3280A, BMS-936559, MEDI4736, MSB0010718C。
KEYTRUDA/ pyridine aldoxime methyliodide (PAM) monoclonal antibody (pembrolizumab) is a kind of anti-PD-1 antibody, is sold by Merck for treating Lung cancer.The amino acid sequence and application method of pyridine aldoxime methyliodide (PAM) monoclonal antibody are disclosed in U.S. Patent number 8,168,757.
It is by the immune for having of Bristol Myers Squibb sale that Opdivo/, which receives Wu Dankang (nivolumab), Enhance active negative immune and adjusts human cell surface receptor PD-1 (programmed death-1 or apoptosis -1/PCD- 1) complete human monoclonal antibodies.Military monoclonal antibody of receiving by its ligand PD-L1 and PD-L2 combine and block PD-1 (Ig superfamily across Memebrane protein) activation, lead to the activation of T cell and for tumour cell or the cell-mediated immune response of pathogen.Activation PD-1 by inhibiting P13k/Akt pathway activation negative regulator T cell activation and effector functions.Receive other titles of military monoclonal antibody It include: BMS-936558, MDX-1106 and ONO-4538.Receive military monoclonal antibody amino acid sequence and using and preparation method disclose In United States Patent (USP) US8,008,449.
Another or a variety of active ingredients for combining or being co-administered with CD73 inhibiting compound of the invention Other examples of (antitumor agent) are immunomodulators.
" immunomodulator " refers to any substance of the monoclonal antibody including influencing immune system as used herein.This hair Bright ICOS binding protein is considered immunomodulator.Immunomodulator can be used as the antitumor for the treatment of cancer Agent.For example, immunomodulator includes but is not limited to anti-CTLA-4 antibody, for example, her monoclonal antibody (ipilimumab, YERVOY) and Anti- PD-1 antibody (Opdivo/ receive military monoclonal antibody and Keytruda/ pyridine aldoxime methyliodide (PAM) monoclonal antibody).Other immunomodulators include but is not limited to OX- 40 antibody, PD-L1 antibody, LAG3 antibody, TIM-3 antibody, 41BB antibody and GITR antibody.
Yervoy (her monoclonal antibody) is the complete people CTLA-4 antibody sold by Bristol Myers Squibb.Her list Anti- protein structure and the method used are described in U.S. Patent number 6,984,720 and 7,605,238.
CD134, also referred to as OX40 antibody (ANTIBODIES TO OX40), are the members of the TNFR- superfamily of receptor, with CD28 is different, is not constitutive expression on the Naive T cells of tranquillization.OX40 antibody is secondary costimulatory molecules, is being swashed It is expressed after 24 to 72 hours after work；Its ligand, OX40L antibody are not also expressed on tranquillization antigen presenting cell, but in its activation After express.The expression of OX40 antibody depends on the complete activation of T cell；There is no a CD28, the expression of OX40 antibody be delayed by and Level reduces four times.OX-40 antibody, OX-40 fusion protein and its application method are disclosed in U.S. Patent number: US 7,504, 101；US 7,758,852；US 7,858,765；US 7,550,140；US 7,960,515；WO2012027328； WO2013028231。
Another or a variety of active ingredients for combining or being co-administered with CD73 inhibiting compound of the invention Other examples of (antitumor agent) are Toll-like receptor 4 (TLR4) antagonists.
Known aminoalkyl glucosaminide phosphate (AGP) can be used as vaccine adjuvant and immunostimulant, for stimulating Cell factor generation, activating macrophage promote innate immune responses and enhance the antibody generation in immune animal.Aminoalkyl GLUCAS AMINECP (AGP) is the synthetic ligands of Toll-like receptor 4 (TLR4).AGP and its immunological regulation by TLR4 It acts in patent disclosure and discloses, such as WO 2006/016997, WO 2001/090129 and/or United States Patent (USP) 6,113,918, And it reports in the literature.Other AGP derivative is disclosed in United States Patent (USP) 7,129,219,6,525,028 and of United States Patent (USP) In United States Patent (USP) 6,911,434.Some AGP serve as the agonist of TLR4, and other AGP are considered as TLR4 antagonist.
Another or a variety of active ingredients for combining or being co-administered with CD73 inhibiting compound of the invention Other examples of (antitumor agent) are the antibody of ICOS.
The CDR of the mouse antibody for people ICOS with agonist activity is shown in PCT/EP2012/055735 (WO2012/131004) in.The antibody of ICOS be also disclosed in WO2008/137915, WO2010/056804, EP1374902, In EP1374901 and EP1125585.
For the other of other active constituents (antitumor agent) with formula (I) compound combination or co-administered of the invention Example is STING modulating compound, CD39 inhibitor and A2a and A2a adenosine antagonist.
In one embodiment, it is desirable that the cancer treatment method of the invention of protection includes co-administration formula (I) compound And/or its pharmaceutically acceptable salt and at least one antitumor agent, such as one kind selected from the group below: anti-micro-pipe agent, platinum coordination Complex compound, alkylating agent, antibiotic agent, Topoisomerase II inhibitors, antimetabolite, topoisomerase I inhibitor, hormone and swash Plain analog, nonreceptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agent, promotees apoptosis at signal transduction pathway inhibitor Agent, cell cycle signals conduction depressant drug；Proteasome inhibitor；With the inhibitor of cancer metabolism.
Formula (I) compound and its pharmaceutically acceptable salt can be known to be used in treatment β hemoglobinopathy at least one Other activating agent co-administereds, the β hemoglobinopathy such as drepanocytosis, sickle-cell anemia and the Mediterranean β be poor Blood.
The example of other active components for combining or being co-administered with the present composition is hydroxycarbamide.
Composition
Pharmaceutical active compounds in the scope of the invention can be used as in the mammal (the especially mankind) for having this to need Selective d NMT1 inhibitor.
The present invention provide containing pharmaceutically acceptable excipient and a effective amount of formula as described above (I) compound or its The pharmaceutical composition of pharmaceutically acceptable salt.
The present invention provides the method for preparation pharmaceutical composition, which contains pharmaceutically acceptable excipient With a effective amount of formula (I) compound as described above or its pharmaceutically acceptable salt, this method include make formula (I) compound or Its pharmaceutically acceptable salt is in conjunction with pharmaceutically acceptable excipient.
Therefore, the present invention provides the method for syndrome and the other illnesss for needing DNMT1 to inhibit before treating cancer, cancer, Including giving a effective amount of formula (I) compound or its pharmaceutically acceptable salt.Formula (I) compound additionally provides the above-mentioned disease for the treatment of The method of diseased state, because they have the ability as DNMT1 inhibitor.It can be by any conventional administration route by drug Patient in need is given, including but not limited to intravenously, intramuscular, oral, local, subcutaneous, intradermal, intraocular and parenteral.
Pharmaceutical active compounds of the invention are mixed in convenient dosage form, such as capsule, tablet or injectable formulation.Make With solid or liquid pharmaceutical carrier.Solid carrier include starch, lactose, calcium sulfate dihydrate, land plaster, sucrose, talcum powder, Gelatin, agar, pectin, Arabic gum, magnesium stearate and stearic acid.Liquid-carrier includes syrup, peanut oil, olive oil, salt water And water.Similarly, carrier or diluent may include any extended release material, such as the monostearate individually or together with wax is sweet Grease or distearin.The amount of solid carrier changes very greatly, but preferably every dosage unit about 25mg to about 1g.Work as use When liquid-carrier, preparation will be aqueous or non-aqueous in syrup, elixir, emulsion, Perle, sterile injection liquid such as ampoule The form of property liquid suspension.
Pharmaceutical composition is prepared according to the routine techniques of Pharmaceutical Chemist, including as necessary for the mixed of tablet form Close, granulation and compacting, or it is appropriate when mixing, filling and solvent components, obtain required oral or extra-parenteral product.
Dosage of the pharmaceutical active compounds in pharmaceutical dosage unit present invention as described above is effective, nontoxic Amount, is preferably selected from 0.001-500mg/kg reactive compound, preferably 0.01-100mg/kg.When treatment needs DNMT1 inhibitor When human patients, selected dosage is preferably 1-6 times daily, administered orally or parenterally.The preferred form of parenteral administration includes office Portion, rectum, transdermal, injection and continuous infusion.Oral dosage units for mankind's administration preferably comprise 0.5 to 3500mg activity Compound.It is suitble to the oral dosage units of mankind's administration to preferably comprise 0.5 to 1,000mg reactive compound.Use relatively low-dose Oral administration be preferred.However, the parenteral administration of high dose also can be used when to patient safety and at one's leisure.
Those skilled in the art can readily determine that optimal dose to be administered, and press down with the specific DMNT1 used Preparation, the intensity of preparation, the progress of method of application and disease symptom and change.Depending on the particular patient treated other because Element, which will lead to, needs to adjust dosage, and the factor includes patient age, weight, diet and administration time.
The method of the present invention of induction DNMT1 inhibitory activity includes this active to needing in mammal (including people) Subject applies the pharmaceutical active compounds of the invention of effective DNMT1 amount of suppression.
The present invention also provides formula (I) compounds or its pharmaceutically acceptable salt in medicine of the preparation as DNMT1 inhibitor Purposes in object.
The present invention also provides formula (I) compounds or its pharmaceutically acceptable salt for treatment.
The present invention also provides formula (I) compound or its pharmaceutically acceptable salts, before being used to treat treating cancer and cancer Syndrome.
The present invention also provides formula (I) compounds or its pharmaceutically acceptable salt before preparing for treating cancer and cancer Purposes in the drug of phase syndrome.
The present invention also provides formula (I) compound or its pharmaceutically acceptable salt in preparation for treating β-hemoglobinopathy Such as the purposes in drepanocytosis, sickle cell anemia or β-thalassemia drug.
The present invention also provides be used as DNMT1 inhibitor pharmaceutical composition, it includes formula (I) compound or its pharmaceutically may be used The salt and pharmaceutically acceptable carrier of receiving.
The present invention also provides the pharmaceutical composition for treating cancer, it includes formula (I) compound or its can pharmaceutically connect The salt and pharmaceutically acceptable carrier received.
In addition, pharmaceutical active compounds of the invention can be with other active components co-administered, such as known treatment cancer Other compounds of disease, or while being applied in combination with DNMT1 inhibitor known compound with effectiveness.
The present invention also provides pharmaceutical composition, it includes 0.5 to 1,000mg formula (I) compound or its is pharmaceutically acceptable Salt and 0.5 to 1,000mg pharmaceutically acceptable excipient.
Without being further described, it is believed that the description that front can be used in those skilled in the art maximally utilises The present invention.Therefore, following embodiment is only interpreted as illustrative, rather than is limited the scope of the invention in any way.
Embodiment
Following example illustrate the present invention.These embodiments are not limited to the scope of the present invention, but are ability Field technique personnel provide the guidance for making and using the compounds of this invention, composition and method.Although describing spy of the invention Embodiment is determined, it will be appreciated, however, by one skilled in the art that without departing from the spirit and scope of the present invention, can carry out Various changes and modifications.
Embodiment 1:
2- [(6- amino -3,5- dicyano -4- ethylpyridine -2- base) sulfanyl] -2- phenyl-acetamides
The compound is purchased from commercial source；CAS184530-72-1.The compound can also according to V.D.Dyachenko, S.G.Krivokolysko, V.P.Litvinov, Chemistry of Heterocyclic Compounds, volume 32, the 8th Phase, method preparation in 1996.
Embodiment 2:
(R)-[(6- amino -3,5- dicyano -4- ethylpyridine -2- base) sulfanyl] -2- phenyl-acetamides
By racemic 2- [(6- amino -3,5- dicyano -4- ethylpyridine -2- base) sulfanyl] -2- phenyl-acetamides (39mg) is dissolved in the part 4mg of 1000 parts of volumes, using the methanol and ultrasonic treatment of 1.30mL boiling, then adds for each 4mg Enter 1.30mL ethyl alcohol, 1.30mL normal heptane is then added.(every 4mL) 4 milligrams every carries out about 10 chiral preparations.It uses Chiralpack, IC, 5 micron, (21mm x 250mm), with 70:30 normal heptane: methanol (20mL/min) elutes, and passes through chirality HPLC separates sample.About 300mL reaction mixture in total is collected, is concentrated it to close to drying, then by product in 40 DEG C of Gao Zhen The lower drying of sky, obtains (R) -2- [(3,5- dicyano -4- ethyl -6- morpholino -2- pyridyl group) sulfanyl] -2- phenyl-acetyl Amine (18mg) is white solid.LCMS m/z=338.3 [M+H]+.98%ee chiral purity.Optical activity: -336 ° (C=0.1, DMSO-d6, 23 DEG C).1H NMR(DMSO-d6) δ ppm 7.91 (br.s., 2H), 7.75 (s, 1H), 7.59 (d, J=6.8Hz, 2H), 7.27-7.40 (m, 4H), 5.56 (s, 1H), 2.69 (q, J=7.4Hz, 2H), 1.18 (t, J=7.6Hz, 3H).
Embodiment 3:
2- { [3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base] sulfanyl } -2- phenyl-acetamides
Step 1:3,5- dicyano -4- ethyl -6- pyridone -2- alcohol ammonium
Be added in the solution in water (190mL) to 2- cyanoacetamide (28.6g, 0.34mol) ammonium hydroxide (25%, Aqueous, 10mL) and propionic aldehyde (10g, 0.17mol).Then the reaction solution is stirred in ambient temperature overnight.Simultaneously by solid filtering Washed with cold methanol, be then dried under reduced pressure, obtain 3,5- dicyano -4- ethyl -6- pyridone -2- alcohol ammonium (12g, It 34.3%), is white solid.LCMS m/z=187.9 [M]–。
The chloro- 4- ethylpyridine -3,5- dimethoxy nitrile of step 2:2,6- bis-
3,5- dicyano -4- ethyl -6- pyridone -2- alcohol ammonium (12g, 58.2mmol) is added slowly in sealed tube POCl3(100mL).The mixture is stirred 15 hours at 150 DEG C.The solvent under reduced pressure removes.By the residue down to ice water In.The solid is filtered and be dried to obtain chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile (10.8g, 83%) of 2,6- bis-, is bright orange Color solid.1H NMR (400MHz, CDCl3) δ ppm 3.13 (d, J=7.7Hz, 2H), 1.42 (t, J=7.7Hz, 3H).
Step 3:2- chloro- 6- (dimethylamino) -4- ethylpyridine -3,5- dimethoxy nitrile
To chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile (1g, 4.44mmol) of 2,6- bis- at n,N-Dimethylformamide (10mL) In solution in be added dimethylamine (tetrahydrofuran solution of 2M, 2.2mL, 4.44mmol) and triethylamine (0.62mL, 4.44mmol).The reaction is stirred at room temperature 5 minutes.Water is added in the reaction.The solid is filtered and is used flash column chromatography Purifying, with petroleum ether: ethyl acetate=3:1 is eluted, and obtains 2- chloro- 6- (dimethylamino) -4- ethylpyridine -3,5- dimethoxy nitrile (900mg, 87%).LCMS m/z=234.9 [M+H]+。
Step 4:2- hydroxyl -2- phenyl-acetamides
CH is added dropwise in the solution in MeOH (140mL) to 2- hydroxyl -2- phenylacetic acid (20g, 0.13mol)3COCl (27.9g, 0.36mol).Then the solution is stirred at room temperature 20 hours.Acquired solution is concentrated to get solid, is dissolved in MeOH(60mL).NH is added3·H2O(140mL).The mixture is stirred 18 hours at 4 DEG C.The mixture is concentrated to get 2- Hydroxyl -2- phenyl-acetamides (20g, 100% yield), are white solid.LCMS m/z=152.0 [M+H]+。
Step 5: methanesulfonic acid 2- amino -2- oxo -1- phenylethylester
To 2- hydroxyl -2- phenyl-acetamides (20g, 0.13mmol) in CH3Three are added in solution in-CN (400mL) Ethamine (36mL, 0.26mmol) and MsCl (18.2g, 0.16mol).Then the mixture is stirred 6 hours at 40 DEG C.Removing should Solvent and by the residue DCM and H2O dissolution, organic layer are washed with brine, and are dried and concentrated, are obtained methanesulfonic acid 2- amino- 2- oxo -1- phenylethylester (15g), is white solid.LCMS m/z=247 [M+Na]+。
Step 6:2- { [3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base] sulfanyl } -2- phenyl second Amide
By 2- chloro- 6- (dimethylamino) -4- ethylpyridine -3,5- dimethoxy nitrile (450mg, 1.92mmol) and KSAc The solution of (263mg, 2.31mmol) in n,N-Dimethylformamide (20mL) is stirred at room temperature 30 minutes, then by methanesulfonic acid 2- amino -2- oxo -1- phenylethylester (528mg, 1.06mmol) and triethylamine (0.53mL, 3.84mmol) add to the solution In.The mixture is stirred at room temperature overnight, is then diluted with water (20mL).The solid by filtration of precipitation is collected and passed through Silica gel chromatography (is eluted) with DCM:MeOH=20:1, obtains 2- { [3,5- dicyano -6- (dimethylamino) -4- ethyls Pyridine -2- base] sulfanyl } -2- phenyl-acetamides (400mg, 57%).LCMS m/z=365.9 [M+H]+。1H NMR (400MHz, CDCl3) δ ppm 7.47-7.43 (m, 2H), 7.42-7.34 (m, 3H), 6.55 (b r s, 1H), 5.60 (br s, 1H), 5.43 (s, 1H), 3.40 (s, 6H), 2.92 (q, J=7.6Hz, 2H), 1.32 (t, J=7.6Hz, 3H).
Embodiment 4:
2- ((3,5- dicyano -4- cyclopropyl -6- (1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide
Step 1:3,5- dicyano -4- cyclopropyl -6- pyridone -2- alcohol ammonium
To cyclopanecarboxaldehyde (47.3g, 562mmol) in H2NH is added in mixture in O (320mL)3·H2O(16mL) With 2- cyanoacetamide (20g, 285mmol).The mixture is stirred at room temperature overnight.The solid is filtered and is washed with cold MeOH It washs, obtains 3,5- dicyano -4- cyclopropyl -6- pyridone -2- alcohol ammonium, be white solid (20g, 32%).LCMS m/z =199.9 [M]–。
The chloro- 4- cyclopropyl pyridine -3,5- dimethoxy nitrile of step 2:2,6- bis-
3,5- dicyano -4- cyclopropyl -6- pyridone -2- alcohol ammonium (20g, 91.7mmol) is added into POCl3(500mL) In, then the mixture is stirred overnight in sealed tube at 150 DEG C.The solvent in vacuo removes.By the residue down to ice water In.It will be formed by solid filtering, be washed with water, be dried to obtain chloro- 4- cyclopropyl pyridine -3, the 5- dimethoxy nitrile (21g) of 2,6- bis-, It is yellow solid.1H NMR (400MHz, CDCl3) δ ppm 2.36-2.27 (m, 1H), 1.51-1.44 (m, 4H).
Step 3:4- (the chloro- 3,5- dicyano -4- cyclopropyl pyridine -2- base of 6-) -1,4- Diazesuberane -1- formic acid uncle Butyl ester
To chloro- 4- cyclopropyl pyridine -3, the 5- dimethoxy nitrile (2.37g, 10mmol) of 2,6- bis- in N.N- dimethylformamide Be added in solution in (50mL) Isosorbide-5-Nitrae-Diazesuberane -1- t-butyl formate (2g, 10mmol) and triethylamine (1.4mL, 10mmol).Then the mixture is stirred at room temperature 5 minutes.Water is added in the reaction, is extracted with ethyl acetate.It will be organic Layer water and salt water washing, it is dry, it is concentrated and (is eluted with petroleum ether: ethyl acetate=5:1) with flash column chromatography, obtained 4- (chloro- 3, the 5- dicyano -4- cyclopropyl pyridine -2- base of 6-)-Isosorbide-5-Nitrae-Diazesuberane -1- t-butyl formate (3.4g, It 85%), is white solid.LCMS m/z=424.0 [M+H]+。
Step 4:4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine - 2- yl) -1,4- Diazesuberane -1- t-butyl formate
By 4- (the chloro- 3,5- dicyano -4- cyclopropyl pyridine -2- base of 6-) -1,4- Diazesuberane -1- t-butyl formate The solution of (600mg, 1.5mmol) and KSAc (205mg, 1.8mmol) in n,N-Dimethylformamide (15mL) is stirred in room temperature It mixes 30 minutes.Addition methanesulfonic acid 2- amino -2- oxo -1- phenylethylester (synthesis is described in 3 step 5 of embodiment, 377mg, 1.6mmol), triethylamine (0.42mL, 3mmol) then is added, then the mixture is stirred at room temperature 2 hours.Add Enter water, (is eluted with petroleum ether: ethyl acetate=2:3) by solid stirring, filtering and with flash column chromatography, obtain 4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine -2- base) -1,4- diaza Cycloheptane -1- t-butyl formate (300mg, 38%), is white solid.LCMS m/z=533.0 [M+H]+.
Step 5:2- ((3,5- dicyano -4- cyclopropyl -6- (1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides
To 4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine -2- Base)-Isosorbide-5-Nitrae-Diazesuberane -1- t-butyl formate (300mg, 0.56mmol) is added three in the solution in DCM (10mL) Fluoroacetic acid (1mL).The reaction solution is stirred at room temperature overnight.Solvent saturation NaHCO3Aqueous solution and salt water washing, it is dense Contract and (eluted with DCM:MeOH=10:1) with flash column chromatography, obtain 2- ((3,5- dicyano -4- cyclopropyl -6- (1, 4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides (170mg, 70%) are white solid. LCMS m/z=433.0 [M+H]+。1H NMR (400MHz, CDCl3) δ ppm 7.46-7.33 (m, 5H), 6.66 (br s, 1H), 5.78 (br s, 1H), 5.34 (s, 1H), 4.10-3.88 (m, 4H), 3.19 (t, J=5.3Hz, 2H), 2.99-2.91 (m, 2H), 2.12-1.94 (m, 4H), 1.33-1.24 (m, 2H), 1.15-1.06 (m, 2H).
Embodiment 5:
2- { [3,5- dicyano -4- cyclopropyl -6- (4- ethyl -1,4- Diazesuberane -1- base) pyridine -2- base] sulphur Alkyl } -2- phenyl-acetamides
To 2- ((3,5- dicyano -4- cyclopropyl -6- (1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides (synthesis, 120mg, 0.28mmol are described in embodiment 4, step 5) add in the solution in DCM (5mL) Enter CH3CHO (37mg, 0.84mmol) and NaBH (OAc)3(119mg, 0.56mmol).The reaction is stirred at room temperature overnight.It will Acquired solution saturation NaHCO3Aqueous solution, water and salt water washing.The solvent is removed and by the residue flash column chromatography It purifies (being eluted with DCM:MeOH=10:1), obtains 2- { [3,5- dicyano -4- cyclopropyl -6- (4- ethyls-Isosorbide-5-Nitrae-diazacyclo Heptane -1- base) pyridine -2- base] sulfanyl } -2- phenyl-acetamides (17mg, 13%) are white solid.LCMS m/z= 460.8[M+H]+。1H NMR (400MHz, CDCl3) δ ppm 7.48-7.31 (m, 5H), 6.64 (br s, 1H), 5.91 (br s, 1H), 5.36 (s, 1H), 4.08-3.84 (m, 4H), 2.97-2.83 (m, 2H), 2.75-2.58 (m, 4H), 2.15-2.01 (m, 3H), 1.31-1.24 (m, 2H), 1.15-1.04 (m, 5H).
Embodiment 6:
2- ((3,5- dicyano -4- ethyl -6- (4- propyl -1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides
Step 1:2- [(the bromo- 3,5- dicyano -4- ethyl -2- pyridyl group of 6-) sulfanyl] -2- phenvl-acetamide
2- [(6- amino -3,5- dicyano -4- ethyl -2- pyridyl group) sulfanyl] -2- phenvl-acetamide (is being implemented Synthesis, 150mg, 0.44mmol are described in example 2) suspension of stirring in anhydrous acetonitrile (8mL) is with copper bromide (II) The processing of (168mg, 0.75mmol) and nitrite tert-butyl (0.09mL, 0.78mmol), is then heated under 70 DEG C of nitrogen atmospheres 15 minutes.The product mixture is cooled to environment temperature, dry method loading to SiO2(1g) and in SiO2Upper carry out chromatogram purification (4g RediSep column) obtains 2- [(bromo- 3, the 5- dicyano -4- ethyl -2- pyrrole of 6- with 20-100%EtOAc/ iso-hexane Piperidinyl) sulfanyl] -2- phenvl-acetamide (55mg, 31% yield) is pale solid.LCMS m/z=401.0 [M- H]–。
Step 2:2- ((3,5- dicyano -4- ethyl -6- (4- propyl -1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides
By 2- [(bromo- 3, the 5- dicyano -4- ethyl -2- pyridyl group of 6-) sulfanyl] -2- phenvl-acetamide (31mg, 0.08mmol) 1- propyl-Isosorbide-5-Nitrae-Diazesuberane the base (0.03mL, 0.19mmol) of the solution in tetrahydrofuran (1mL) It handles and is stirred at room temperature 2 hours.By product mixture concentration and loading is to SiO2(0.9g) and in SiO2Upper carry out chromatographically pure Change (4g RediSep column, with 0-10%MeOH, 0-0.1%NH3/CH2Cl2Elution) and with triturated under ether, obtain 2- [[3,5- bis- Cyano -4- ethyl -6- (4- propyl -1,4- Diazesuberane -1- base) -2- pyridyl group] sulfanyl] -2- phenvl-acetamide (27mg, 76% yield), is white solid.LCMS m/z=461.2 [M-H]–。1H NMR (300MHz, DMSO-d6)δppm 7.92 (s, 1H), 7.54-7.45 (m, 2H), 7.43-7.30 (m, 4H), 5.51 (s, 1H), 3.89 (br s, 4H), 2.77 (q, J =7.4Hz, 4H), 2.68-2.53 (m, 2H), 2.47-2.17 (m, 2H), 1.91 (br s, 2H), 1.42 (br s, 2H), 1.20 (t, J=7.5Hz, 3H), 0.83 (br t, J=7.3Hz, 3H).
Embodiment 7:
2- { [3,5- dicyano -4- ethyl -6- (4- ethyl -1,4- Diazesuberane -1- base) pyridine -2- base] sulfane Base } -2- phenyl-acetamides
By 2- [(the bromo- 3,5- dicyano -4- ethyl -2- pyridyl group of 6-) sulfanyl] -2- phenvl-acetamide (in embodiment 6, synthesis, 32mg, 0.08mmol are described in step 1) solution N- ethyl homopiperazine in tetrahydrofuran (1mL) (0.03mL, 0.20mmol) is handled and is stirred 2 hours in environment temperature.By the product mixture loading to SiO2(0.9g) and SiO2Upper progress chromatogram purification (4g RediSep column 0-10%MeOH, 0-0.1%NH3/CH2Cl2Elution), obtain 2- [[3, 5- dicyano -4- ethyl -6- (4- ethyl -1,4- Diazesuberane -1- base) -2- pyridyl group] sulfanyl] -2- phenyl-acetyl Amine (33mg, 94% yield), is white solid.LCMS m/z=447.2 [M-H]–。1H NMR (300MHz, DMSO-d6)δ Ppm 7.93 (s, 1H), 7.54-7.42 (m, 2H), 7.47-7.30 (m, 4H), 5.51 (s, 1H), 4.09-3.79 (m, 4H), 3.02-2.64 (m, 8H), 2.02 (br s, 2H), 1.22 (t, J=7.5Hz, 3H), 1.08 (br t, J=6.8Hz, 3H).
Embodiment 8:
2- { [3,5- dicyano -4- ethyl -6- (5- oxo -1,4- Diazesuberane -1- base) pyridine -2- base] sulfane Base } -2- phenyl-acetamides
Step 1: chloro- 4- ethyl -6- (5- oxo -1,4- Diazesuberane -1- base) pyridine -3,5- dimethoxy nitrile
To chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in embodiment 3, step 2,225mg, 1mmol) and Isosorbide-5-Nitrae-diaza cycloheptyl is added dropwise in triethylamine (202mg, 2mmol) in the agitating solution in methylene chloride (10mL) Alkane -5- ketone (114mg, 1mmol).Acquired solution is stirred at room temperature overnight.The reaction is quenched with HCl solution (6N), then It is extracted with methylene chloride (40mL).Organic layer is washed with salt water (30mL), is then dried, filtered and is depressurized with anhydrous sodium sulfate Concentration.By the residue with silica gel chromatography (petrol ether/ethyl acetate=5:1), chloro- 4- ethyl -6- (5- oxo-is obtained Isosorbide-5-Nitrae-Diazesuberane -1- base) pyridine -3,5- dimethoxy nitrile (150mg, 50%) .LCMS m/z=304 [M+H]+。
Step 2:2- { [3,5- dicyano -4- ethyl -6- (5- oxo -1,4- Diazesuberane -1- base) pyridine -2- Base] sulfanyl } -2- phenyl-acetamides
At 0 DEG C, to agitating solution of the thioacetic acid potassium (114mg, 1.0mmol) in n,N-Dimethylformamide (20mL) It is middle be added dropwise chloro- 4- ethyl -6- (5- oxo-Isosorbide-5-Nitrae-Diazesuberane -1- base) pyridine -3,5- dimethoxy nitrile (150mg, 0.5mmol) the solution in N,N-dimethylformamide (5mL).By acquired solution environment temperature stir 2 hours, then plus Enter potassium carbonate (138mg, 1.0mmol) and methanesulfonic acid 2- amino -2- oxo -1- phenylethylester (is retouched in 3 step 5 of embodiment Synthesis, 344mg, 3.0mmol are stated).Gained mixture is stirred at room temperature overnight.By the reaction with HCl solution (1N, 60mL) It is quenched, is then extracted with ethyl acetate (40mL).Organic layer is washed and is concentrated to dryness with salt water (30mL).The residue is used Preparative-HPLC purifying, obtains 2- { [3,5- dicyano -4- ethyl -6- (5- oxo-Isosorbide-5-Nitrae-Diazesuberane -1- base) pyrrole Pyridine -2- base] sulfanyl } -2- phenyl-acetamides (85mg) are white solid.LCMS m/z=435 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 1.23 (m, 3H), 2.68 (s, 2H), 2.79 (m, 2H), 3.35 (s, 2H), 4.00 (s, 4H), 5.53 (s, 1H), 7.40 (m, 3H), 7.51 (m, 2H), 7.74 (s, 1H), 7.93 (s, 1H).
Embodiment 9:
2- ((3,5- dicyano -4- cyclopropyl -6- morpholino pyridine -2- base) sulfenyl) -2- (pyridin-4-yl) acetamide
Step 1:2- (pyridin-4-yl) -2- ((trimethyl silyl) oxygroup) acetonitrile
By Pyridine-4-Carboxaldehyde (3.5g, 32.7mmol), TMS-CN (163.3mmol) in CHCl3Mixture in (50mL) It is stirred 12 hours at 50 DEG C.Gained mixture is concentrated.By residue silica gel column purification, with petrol ether/ethyl acetate= 20/1 elution, obtains 2- (pyridin-4-yl) -2- ((trimethyl silyl) oxygroup) acetonitrile (1.8g, 22% yield), is nothing Color oil.LCMS m/z=207 [M+H]+。
Step 2:2- hydroxyl -2- (pyridin-4-yl) acetamide
To dense H2SO4Agitating solution in (90%, 10mL) be added 2- (pyridin-4-yl) -2- ((trimethyl silyl) Oxygroup) acetonitrile (1.8g, 8.72mmol).Gained mixture is stirred at room temperature 5 hours.It is subsequently poured into ice water and uses NH3· H2O alkalizes to pH 9.The solution is concentrated, by residue silica gel column purification, uses CH2Cl2/ MeOH (30/1) elution, obtains 2- hydroxyl -2- (pyridin-4-yl) acetamide (900mg, 53% yield), is white solid.LCMS m/z=153 [M+H]+。
Step 3: methanesulfonic acid 2- amino -2- oxo -1- (pyridin-4-yl) ethyl ester
At 0 DEG C, to 2- hydroxyl -2- (pyridin-4-yl) acetamide (900mg, 5.91mmol), Et3N (1.79g, MsCl (745mg, 6.5mmol) 17.7mmol) is added in the stirring mixture in tetrahydrofuran (25mL).By gained mixture It is stirred at room temperature 2 hours.The reaction mixture is concentrated.By residue silica gel column purification, CH is used2Cl2/MeOH(70/10) Elution, obtains methanesulfonic acid 2- amino -2- oxo -1- (pyridin-4-yl) ethyl ester (800mg, 59% yield), is brown oil. LCMS m/z=231 [M+H]+。
The chloro- 4- cyclopropyl -6- morpholino pyridine -3,5- dimethoxy nitrile of step 4:2-
To chloro- 4- cyclopropyl pyridine -3, the 5- dimethoxy nitrile (10g, 42.2mmol) of 2,6- bis- in n,N-Dimethylformamide Morpholine (3.7g, 42.2mmol) and triethylamine (4.3g, 42.2mmol) are added in solution in (200mL).By the reaction solution It is stirred at room temperature 5 minutes.Water is added in the reaction and filters obtained solid, be washed with water and is dried to obtain the chloro- 4- ring of 2- Propyl -6- morpholino pyridine -3,5- dimethoxy nitrile is yellow solid (9.3g, 77% yield) .LCMS m/z=289 [M+H]+.
Step 5:2- ((3,5- dicyano -4- cyclopropyl -6- morpholino pyridine -2- base) sulfenyl) -2- (pyridin-4-yl) second Amide
By chloro- 4- cyclopropyl -6- morpholino pyridine -3, the 5- dimethoxy nitrile (200mg, 0.69mmol) of 2-, KSAc (788mg, 0.69mmol) mixture in N,N-dimethylformamide (8mL) is stirred at room temperature 30 minutes.Then methanesulfonic acid 2- ammonia is added Base -2- oxo -1- (pyridin-4-yl) ethyl ester (191mg, 0.83mmol) and triethylamine (209mg, 202mmol).Gained is mixed Object is closed to be stirred at room temperature 12 hours.By the reaction mixture down in water (50mL), then extracted with EtOAc (50mL x 2). By combined organic layer drying, concentration and by residue silica gel column purification, CH is used2Cl2/ MeOH (50/1) elution, obtains 2- ((3,5- dicyano -4- cyclopropyl -6- morpholino pyridine -2- base) sulfenyl) -2- (pyridin-4-yl) acetamide (100mg, 34% Yield), it is white solid.LCMS m/z=421 [M+H]+。1H NMR (400MHz, DMSO) δ ppm 8.58 (dd, J=4.6, 1.4Hz, 2H), 8.04 (br s, 1H), 7.55-7.45 (m, 3H), 5.57 (s, 1H), 3.80 (m, 4H), 3.71-3.56 (m, 4H), 2.16-2.08 (m, 1H), 1.16-1.07 (m, 2H), 1.02-0.93 (m, 2H).
Embodiment 10
2- { [3,5- dicyano -4- ethyl -6- (4- methyl -3- oxypiperazin -1- base) pyridine -2- base] sulfanyl } -2- (pyridin-4-yl) acetamide
The chloro- 4- ethyl -6- of step 1:2- (4- methyl -3- oxypiperazin -1- base) pyridine -3,5- dimethoxy nitrile
By chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in 3 step 2 of embodiment, 226mg, 1.000mmol), 1- methyl piperazine -2- ketone (114mg, 1.000mmol) and triethylamine (0.167mL, 1.200mmol) are in N, N- Solution in dimethylformamide (8mL) is stirred at room temperature 30 minutes.By the reaction mixture down in water (50mL) and using second Acetoacetic ester (50mL x 2) extraction, combined organic layer is dry, it is concentrated to get required product (270mg, 89% yield), is White solid.LCMS m/z=304.0 [M+H]+.
Step 2:2- { [3,5- dicyano -4- ethyl -6- (4- methyl -3- oxypiperazin -1- base) pyridine -2- base] sulfane Base } -2- (pyridin-4-yl) acetamide
By thioacetic acid potassium (122mg, 1.067mmol), the chloro- 4- ethyl -6- of 2- (4- methyl -3- oxypiperazin -1- base) Pyridine -3,5- dimethoxy nitrile (describing synthesis, 270mg, 0.889mmol in 9 step 3 of embodiment) is in n,N-Dimethylformamide Solution in (10mL) is stirred at room temperature 30 minutes, then by methanesulfonic acid 2- amino -2- oxo -1- (pyridin-4-yl) ethyl ester (246mg, 1.067mmol) and triethylamine (0.248mL, 1.778mmol) add to the solution.The reaction mixture is stirred in room temperature It mixes 12 hours.The reaction mixture is extracted down in water (50mL) and with ethyl acetate (50mL x 2), by the organic of merging Layer is dry, concentration, by residue silica gel column purification, is eluted with DCM/MeOH (30/1), obtains 2- { [3,5- dicyano -4- Ethyl -6- (4- methyl -3- oxypiperazin -1- base) pyridine -2- base] sulfanyl } -2- (pyridin-4-yl) acetamide (50mg, 13% yield), it is white solid.LCMS m/z=435.8 [M+H]+。1H NMR (400MHz, CDCl3) δ ppm8.64 (d, J =3.8Hz, 2H), 7.47 (d, J=5.3Hz, 2H), 7.25 (br s, 1H), 6.14 (br s, 1H), 5.50 (s, 1H), 4.43 (dd, J=56.9,17.3Hz, 2H), 4.26-4.17 (m, 1H), 4.18-4.08 (m, 1H), 3.58-3.47 (m, 2H), 3.03 (s, 3H), 2.96 (q, J=7.6Hz, 2H), 1.34 (t, J=7.6Hz, 3H).
Embodiment 11
2- [(3,5- dicyano -4- ethyl -6- { methyl [2- (morpholine -4- base) ethyl] amino } pyridine -2- base) sulfane Base] -2- phenyl-acetamides
The chloro- 4- ethyl -6- of step 1:2- (methyl (2- morpholinoethyl) amino) pyridine -3,5- dimethoxy nitrile
In room temperature, to chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (in 3 step 2 of embodiment describe synthesis, 300mg, 1.327mmol) and N- methyl -2- morpholino ethamine (191mg, 1.327mmol) in n,N-Dimethylformamide Et is added in solution in (15mL)3Simultaneously gained mixture is stirred at room temperature 1 hour by N (0.185mL, 1.327mmol).It should Reaction mixture is extracted down in water (50mL) and with ethyl acetate (50mL x 2), and combined organic layer is dried and concentrated, Obtaining required product (320mg, 72% yield) is pale solid.LCMS m/z=334 [M+H]+.
Step 2:2- [(3,5- dicyano -4- ethyl -6- { methyl [2- (morpholine -4- base) ethyl] amino } pyridine -2- base) Sulfanyl] -2- phenyl-acetamides
By thioacetic acid potassium (82mg, 0.719mmol), the chloro- 4- ethyl -6- of 2- (methyl (2- morpholinoethyl) amino) pyrrole Solution of pyridine -3, the 5- dimethoxy nitrile (200mg, 0.599mmol) in n,N-Dimethylformamide (10mL) is stirred at room temperature 30 points Clock, then by methanesulfonic acid 2- amino -2- oxo -1- phenylethylester (describe synthesis in 3 step 5 of embodiment, 165mg, 0.719mmol) and triethylamine (0.167mL, 1.198mmol) adds to the solution.It is small that the reaction mixture is stirred at room temperature 12 When.The reaction mixture is extracted down in water (50mL) and with ethyl acetate (50mL x 2), combined organic layer is dry, Residue silica gel column purification is eluted with DCM/MeOH (30/1), obtains 2- [(3,5- dicyano -4- ethyl -6- by concentration { methyl [2- (morpholine -4- base) ethyl] amino } pyridine -2- base) sulfanyl] -2- phenyl-acetamides (75mg, 27% yield), For white solid.LCMS m/z=465.0 [M+H]+。1H NMR (400MHz, CDCl3) δ ppm 7.48-7.32 (m, 5H), 6.98 (br s, 1H), 5.84 (br s, 1H), 5.41 (s, 1H), 4.20-4.06 (m, 1H), 3.78-3.60 (m, 5H), 3.45 (s, 3H), 2.91 (q, J=7.6Hz, 2H), 2.80-2.65 (m, 2H), 2.62-2.45 (m, 4H), 1.32 (t, J=7.6Hz, 3H).
Embodiment 12
2- { [3,5- dicyano -4- ethyl -6- (4- propylpiperazine -1- base) pyridine -2- base] sulfanyl } -2- phenylacetyl Amine
The chloro- 4- ethyl -6- of step 1:2- (4- propylpiperazine -1- base) pyridine -3,5- dimethoxy nitrile
By chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in 3 step 2 of embodiment, 300mg, 1.32mmol), 1- propylpiperazine hydrochloride (217.8mg, 1.32mmol) and Et3N (133.3mg, 1.32mmol) is in N, N- bis- Mixture in methylformamide (10mL) is stirred at room temperature 1 hour.By gained mixture down in water (50mL), then use EtOAc (50mL x2) extraction, combined organic layer is dried and concentrated to obtain the chloro- 4- ethyl -6- of 2- (4- propylpiperazine -1- Base) pyridine -3,5- dimethoxy nitrile (310mg, 74%) is brown oil.LCMS m/z=318.0 [M+H]+。
Step 2:2- { [3,5- dicyano -4- ethyl -6- (4- propylpiperazine -1- base) pyridine -2- base] sulfanyl } -2- benzene Yl acetamide
By the chloro- 4- ethyl -6- of 2- (4- propylpiperazine -1- base) pyridine -3,5- dimethoxy nitrile (310mg, 0.97mmol) and Solution of the KSAc (134mg, 1.17mmol) in n,N-Dimethylformamide (10mL) is stirred at room temperature 30 minutes, is then added Methanesulfonic acid 2- amino -2- oxo -1- phenylethylester (describing synthesis, 268mg, 0.97mmol in 3 step 5 of embodiment) and Et3Solution of the N (196mg, 1.94mmol) in n,N-Dimethylformamide.The mixture is stirred at room temperature 12 hours.It will The reaction mixture is then extracted with EtOAc (50mL x 2) down in water (50mL), and combined organic layer is dry and dense Contracting.The residue is passed through into silica gel chromatography (CH2Cl2: MeOH 20:1), obtain 2- { [3,5- dicyano -4- ethyl -6- (4- propylpiperazine -1- base) pyridine -2- base] sulfanyl } -2- phenyl-acetamides (100mg, 23%) are white solid.LCMS M/z=488.8 [M+H]+。1H NMR (400MHz, CDCl3) δ ppm 7.48-7.42 (m, 2H), 7.41-7.35 (m, 3H), 6.51 (br s, 1H), 5.68 (br s, 1H), 5.36 (s, 1H), 4.04-3.91 (m, 4H), 2.91 (q, J=7.6Hz, 2H), 2.65- 2.50 (m, 4H), 2.41-2.31 (m, 2H), 1.61-1.47 (m, 2H), 1.32 (t, J=7.6Hz, 3H), 0.93 (t, J= 7.4Hz, 3H).
Embodiment 13:
2- ({ 3,5- dicyano -4- ethyl -6- [4- (piperidin-4-yl) piperazine -1- base] pyridine -2- base } sulfanyl) -2- Phenyl-acetamides
To 2- [(the bromo- 3,5- dicyano -4- ethyl -2- pyridyl group of 6-) sulfanyl] -2- phenvl-acetamide (in embodiment 6 Synthesis, 28mg, 0.0700mmol are described in step 1) and 4- piperazine -1- phenylpiperidines base -1- t-butyl formate (20.68mg, Triethylamine (19.4 μ L, 0.1400mmol) 0.0800mmol) is added in the mixture in tetrahydrofuran (2mL).By the mixing Object stirs 6 hours.Additional 4- piperazine -1- phenylpiperidines base -1- t-butyl formate (4.6mg.0.25 equivalent) and Et is added3N (9.7 μ L, 1 equivalent) simultaneously futher stirs the mixture 16 hours.The mixture is diluted with EtOAc (20mL), with water (3x 20mL), salt water (25mL) washs, and is filtered by Hydrophobic glass funnel and removes the solvent under reduced pressure.The residue is dissolved in DCM And in SiO2Upper progress chromatogram purification (4g RediSep column), uses the DCM solution of 0-10%MeOH as eluant, eluent, obtains The colorless residue of 25mg.The residue is dissolved in DCM (2mL) and trifluoroacetic acid (0.5mL, 6.73mmol) is added.This is mixed It closes object to be stirred at room temperature 1 hour, which be removed, by residue Et2O grinding is simultaneously dried in vacuo at 50 DEG C, is obtained It to pale powder, is dissolved in purifying in DMSO and with preparative HPLC, obtains 2- [[3,5- dicyano -4- ethyl -6- [4- (4- piperidyl) piperazine -1- base] -2- pyridyl group] sulfanyl] -2- phenvl-acetamide (12mg, 0.0245mmol, 35%), For white powder.LCMS m/z=488.3 [M-H]–。1H NMR (300MHz, DMSO-d6) δ ppm 8.37 (s, 1H), 7.94 (s, 1H), 7.52 (d, J=6.7Hz, 2H), 7.45-7.29 (m, 4H), 5.53 (s, 1H), 3.90-3.82 (m, 4H), 3.18-3.04 (m, 2H), 2.96-2.61 (m, 6H), 2.61-2.53 (m, 2H), 2.48-2.16 (m, 1H), 1.81 (br d, J=12.4Hz, 2H), 1.54 (br s, 2H), 1.20 (t, J=7.6Hz, 3H).
Embodiment 14
2- ({ 3,5- dicyano -4- cyclopropyl -6- [3- (hydroxymethyl) piperazine -1- base] pyridine -2- base } sulfanyl) -2- Phenyl-acetamides
Step 1:4- (the chloro- 3,5- dicyano -4- cyclopropyl pyridine -2- base of 6-) -2- (hydroxymethyl) piperazinyl -1- formic acid The tert-butyl ester
In room temperature, to chloro- 4- cyclopropyl pyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (in 4 step 2 of embodiment describe synthesis, 238mg, 1mmol) 2- (hydroxymethyl) piperazinyl -1- formic acid uncle is added in the solution in n,N-Dimethylformamide (8mL) Butyl ester (216mg, 1mmol), is then added Et3N (101mg, 1mmol).The mixture is stirred at room temperature 1 hour.This is anti- Mixture is answered to extract down in water (50mL) and with EtOAc (50mL x 2).Combined organic layer is dried and concentrated, then will Residue silica gel column purification, uses CH2Cl2: MeOH 50:1 elution obtains 4- (chloro- 3, the 5- dicyano -4- cyclopropyl pyrrole of 6- Pyridine -2- base) -2- (hydroxymethyl) piperazinyl -1- t-butyl formate (260mg, 82%) is brown oil.LCMS m/z= 318.0[M+H–Boc]+。
Step 2:4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine - 2- yl) -2- (hydroxymethyl) piperazinyl -1- t-butyl formate
By the tertiary fourth of 4- (the chloro- 3,5- dicyano -4- cyclopropyl pyridine -2- base of 6-) -2- (hydroxymethyl) piperazinyl -1- formic acid The solution of ester (260mg, 0.62mmol) and KSAc (85mg, 0.74mmol) in n,N-Dimethylformamide (10mL) is in room temperature Stirring 30 minutes, then by methanesulfonic acid 2- amino -2- oxo -1- phenylethylester (in 3 step 5 of embodiment describe synthesis, 170mg, 0.74mmol) and Et3N (125mg, 1.24mmol) is added in the solution.The mixture is stirred at room temperature 12 hours, It is subsequently poured into water (50mL) and is extracted with EtOAc (50mL x 2).Combined organic layer is dry, it is concentrated and passes through silicagel column Chromatogram purification (CH2Cl2: MeOH 40:1), obtain 4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyan Base -4- cyclopropyl pyridine -2- base) -2- (hydroxymethyl) piperazinyl -1- t-butyl formate (280mg, 82%), it is solid for white Body.LCMS m/z=570.7 [M+Na]+。
Step 3:2- ({ 3,5- dicyano -4- cyclopropyl -6- [3- (hydroxymethyl) piperazine -1- base] pyridine -2- base } sulfane Base) -2- phenyl-acetamides
In room temperature, to 4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyrrole Pyridine -2- base) -2- (hydroxymethyl) piperazinyl -1- t-butyl formate (280mg, 0.61mmol) is in the solution in DCM (10mL) It is added trifluoroacetic acid (3mL).The mixture is stirred at room temperature 12 hours, is then concentrated in vacuo, with saturation NaHCO3Solution alkali Change and DCM (50mL x2) is used to extract.Combined organic layer is dry, it is concentrated and passes through silica gel chromatography (CH2Cl2:MeOH 30:1), 2- ({ 3,5- dicyano -4- cyclopropyl -6- [3- (hydroxymethyl) piperazine -1- base] pyridine -2- base } sulfanyl)-is obtained 2- phenyl-acetamides (90mg, 32%), are white solid.LCMS m/z=448.8 [M+H]+。1H NMR (400MHz, CD3OD) δ ppm 7.60-7.50 (m, 2H), 7.50-7.31 (m, 3H), 5.54 (s, 1H), 4.69-4.44 (m, 2H), 3.72- 3.55 (m, 2H), 3.32-3.25 (m, 1H), 3.21-2.89 (m, 4H), 2.20-2.10 (m, 1H), 1.28-1.20 (m, 2H), 1.15-1.05 (m, 2H).
Embodiment 15:
2- { [3,5- dicyano -4- cyclopropyl -6- (3- oxypiperazin -1- base) pyridine -2- base] sulfanyl } -2- phenyl second Amide
The chloro- 4- cyclopropyl -6- of step 1:2- (3- oxypiperazin -1- base) pyridine -3,5- dimethoxy nitrile
In room temperature, to chloro- 4- cyclopropyl pyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (in 4 step 2 of embodiment describe synthesis, 237mg, 1mmol) addition piperazine -2- ketone (100mg, 1mmol) in the solution in n,N-Dimethylformamide (10mL), then Et is added3N (0.14mL, 1mmol).The mixture is stirred at room temperature 5 minutes, is then diluted with water and is extracted with EtOAc.It will Combined organic layer water and salt water washing is dried and concentrated to obtain the chloro- 4- cyclopropyl -6- of 2- (3- oxypiperazin -1- base) pyrrole Pyridine -3,5- dimethoxy nitrile (290mg, 96%) .LCMS m/z=301.9 [M+H]+。
Step 2:2- { [3,5- dicyano -4- cyclopropyl -6- (3- oxypiperazin -1- base) pyridine -2- base] sulfanyl } -2- Phenyl-acetamides
By the chloro- 4- cyclopropyl -6- of 2- (3- oxypiperazin -1- base) pyridine -3,5- dimethoxy nitrile (290mg, 0.96mmol) and Solution of the KSAc (132mg, 1.16mmol) in n,N-Dimethylformamide (10mL) is stirred at room temperature 30 minutes, then by first Sulfonic acid 2- amino -2- oxo -1- phenylethylester (describing synthesis, 265mg, 1.16mmol in 3 step 5 of embodiment) and Et3N (0.27mL, 1.92mmol) adds to the solution.The mixture is stirred at room temperature overnight, is then diluted with water (20mL). The solid by filtration of precipitation is collected and is passed through silica gel chromatography (MeOH:DCM=10:1), 2- { [3,5- dicyan are obtained Base -4- cyclopropyl -6- (3- oxypiperazin -1- base) pyridine -2- base] sulfanyl } -2- phenyl-acetamides (48mg, 12%) .LCMS M/z=432.8 [M+H]+。1H NMR (400MHz, CD3OD) δ ppm 7.56 (d, J=6.8Hz, 2H), 7.45-7.35 (m, 3H), 5.57 (s, 1H), 4.48 (q, J=17.8Hz, 2H), 4.21-4.04 (m, 2H), 3.50 (t, J=5.2Hz, 2H), 2.21-2.11 (m, 1H), 1.30-1.22 (m, 2H), 1.14-1.06 (m, 2H).
Embodiment 16
2- ({ 3,5- dicyano -4- cyclopropyl -6- [4- (morpholine -4- base) piperidin-1-yl] pyridine -2- base } sulfanyl) - 2- phenyl-acetamides
The chloro- 4- cyclopropyl -6- of step 1:2- (4- morpholino piperidin-1-yl) pyridine -3,5- dimethoxy nitrile
By chloro- 4- cyclopropyl pyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in 4 step 2 of embodiment, 238mg, 1mmol) 4- (piperidin-4-yl) morpholine dihydrochloride (115mg, 1mmol) and Et3N (303mg, 3mmol) is in N, N- dimethyl methyl Mixture in amide (8mL) is stirred at room temperature 30 minutes.By the reaction mixture down in water (50mL) and using EtOAc (50mL x 2) extraction.Combined organic layer is dried and concentrated to obtain the chloro- 4- cyclopropyl -6- of 2- (4- morpholino piperidines -1- Base) pyridine -3,5- dimethoxy nitrile (320mg, 86%) is brown solid.LCMS m/z=372.1 [M+H]+。
Step 2:2- ({ 3,5- dicyano -4- cyclopropyl -6- [4- (morpholine -4- base) piperidin-1-yl] pyridine -2- base } sulphur Alkyl) -2- phenyl-acetamides
By the chloro- 4- cyclopropyl -6- of 2- (4- morpholino piperidin-1-yl) pyridine -3,5- dimethoxy nitrile (320mg, 0.86mmol) Be stirred at room temperature 30 minutes with solution of the KSAc (117mg, 1.03mmol) in n,N-Dimethylformamide (10mL), then plus Enter methanesulfonic acid 2- amino -2- oxo -1- phenylethylester (describing synthesis, 236mg, 1.03mmol in 3 step 5 of embodiment) And Et3N (174mg, 1.72mmol).Gained mixture is stirred at room temperature 12 hours.The mixture is poured into water (50mL) And it is extracted with EtOAc (50mL x 2).Combined organic layer is dry, then which is passed through silica gel column chromatography by concentration Purify (CH2Cl2: MeOH=50:1), obtain 2- ({ 3,5- dicyano -4- cyclopropyl -6- [4- (morpholine -4- base) piperidin-1-yl] Pyridine -2- base } sulfanyl) -2- phenyl-acetamides (130mg, 30%) are white solid.LCMS m/z=502.8 [M+H ]+。1H NMR (400MHz, CDCl3) δ ppm 7.50-7.43 (m, 2H), 7.43-7.35 (m, 3H), 6.57 (br s, 1H), 5.68 (br s, 1H), 5.37 (s, 1H), 4.65 (d, J=14.1Hz, 2H), 3.82-3.70 (m, 4H), 3.19 (t, J=12.7Hz, 2H), 2.66-2.45 (m, 5H), 2.13-2.02 (m, 3H), 1.70-1.59 (m, 2H), 1.32-1.27 (m, 2H), 1.19-1.14 (m, 2H).
Embodiment 17
2- ((3,5- dicyano -4- ethyl -6- (2,8- diaza spiro [4.5] decyl- 8- yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；2,2,2- trifluoroacetic acid
To 2- [(the bromo- 3,5- dicyano -4- ethyl -2- pyridyl group of 6-) sulfanyl] -2- phenvl-acetamide (in embodiment 6 Synthesis, 30mg, 0.07mmol are described in step 1) and 2,8- diaza spiro [4.5] decyl- 2- t-butyl formate hydrochloride Triethylamine (0.03mL, 0.25mmol) is added in the mixture in tetrahydrofuran (2mL) in (23mg, 0.08mmol).This is anti- Mixture is answered to stir 1 hour.The mixture is diluted with EtOAc (20mL), with water (3x 20mL), saturated sodium-chloride (25mL) Washing, is filtered by Hydrophobic glass funnel and removes the solvent under reduced pressure.By the crude product in SiO2Upper progress chromatogram purification (4g RediSep column), use the CH of 0-10%MeOH2Cl2Solution is as eluant, eluent.Gained residue is dissolved in CH2Cl2(2mL), Then trifluoroacetic acid (0.5mL, 6.73mmol) is added, then stirs subsequent mixture 1 hour in environment temperature.This is molten Agent is removed under reduced pressure and by the product triturated under ether, is dried in vacuo at 50 DEG C, obtains 2- [[3,5- dicyano -6- (2,8- phenodiazines Miscellaneous spiral shell [4.5] decyl- 8- yl) -4- ethyl -2- pyridyl group] sulfanyl] -2- phenvl-acetamide；2,2,2- trifluoroacetic acids (38mg, 88% yield), it is white solid.LCMS m/z=459.3 [M-H]–。1H NMR (300MHz, DMSO-d6)δppm 8.79 (br s, 2H), 7.92 (s, 1H), 7.57-7.47 (m, 2H), 7.44-7.30 (m, 4H), 5.53 (s, 1H), 4.30-3.98 (m, 2H), 3.91-3.60 (m, 2H), 3.43-3.12 (m, 4H), 2.78 (q, J=7.5Hz, 2H), 2.11-1.81 (m, 6H), 1.22 (t, J=7.6Hz, 3H).
Embodiment 18:
2- ((3,5- dicyano -4- cyclopropyl -6- (3- (dimethylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides
Step 1:3- (dimethylamino) piperidyl -1- t-butyl formate
To 3- oxo-piperidine base -1- t-butyl formate (500mg, 2.5mmol) in the solution in methylene chloride (10mL) The tetrahydrofuran solution (3.8mL, 2M, 7.5mmol) of dimethylamine is added.It is stirred at room temperature after five minutes, by NaBH (OAc)3 (1.06g, 5mmol) adds to the mixture.The mixture is stirred at room temperature overnight, be then concentrated in vacuo and passes through silicagel column color Spectrum purifying (CH2Cl2: MeOH=10:1), 3- (dimethylamino) piperidyl -1- t-butyl formate (500mg, 88%) is obtained, For white solid.LCMS m/z=229.0 [M+H]+。
Step 2:N, N- lupetidine -3- amine
To 3- (dimethylamino) piperidyl -1- t-butyl formate (500mg, 2.19mmol) in methylene chloride (4mL) Solution in be added trifluoroacetic acid (4mL).The mixture is stirred at room temperature overnight, is then concentrated in vacuo, with saturation NaHCO3 It is water-soluble basified and be extracted with dichloromethane.Combined organic layer in vacuo is concentrated, N, N- lupetidine -3- amine are obtained (250mg).LCMS m/z=129.1 [M+H]+。
The chloro- 4- cyclopropyl -6- of step 3:2- (3- (dimethylamino) piperidin-1-yl) pyridine -3,5- dimethoxy nitrile
In room temperature, to chloro- 4- cyclopropyl pyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (in 4 step 2 of embodiment describe synthesis, 236mg, 1mmol) it is added N in the solution in n,N-Dimethylformamide (10mL), N- lupetidine -3- amine (128mg, 1mmol), triethylamine (0.14mL1mmol) then is added.The mixture is stirred at room temperature 5 minutes, is then diluted with water.It will The solid by filtration of precipitation collects and passes through silica gel chromatography (CH2Cl2: ethyl acetate=1:1), obtain the chloro- 4- ring of 2- Propyl -6- (3- (dimethylamino) piperidin-1-yl) pyridine -3,5- dimethoxy nitrile (190mg, 58%) .LCMS m/z=329.8 [M +H]+。
Step 4:2- ((3,5- dicyano -4- cyclopropyl -6- (3- (dimethylamino) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides
By the chloro- 4- cyclopropyl -6- of 2- (3- (dimethylamino) piperidin-1-yl) pyridine -3,5- dimethoxy nitrile (190mg, 0.58mmol) it is stirred at room temperature 30 minutes with the solution of KSAc (80mg, 0.7mmol) in n,N-Dimethylformamide (6mL), Then be added methanesulfonic acid 2- amino -2- oxo -1- phenylethylester (describe synthesis in 3 step 5 of embodiment, 159mg, 0.7mmol) and triethylamine (0.16mL, 1.16mmol).The mixture is stirred at room temperature overnight, is then diluted with water.It will analysis Solid by filtration out is collected, and then by silica gel chromatography (methylene chloride: methanol=20:1), obtains 2- ((3,5- Dicyano -4- cyclopropyl -6- (3- (dimethylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- phenyl-acetamides (132mg, 49%).LCMS m/z=460.9 [M+H]+。1H NMR (400MHz, CDCl3) δ ppm 7.49-7.44 (m, 2H), 7.40-7.34 (m, 3H), 5.54 (s, 1H), 5.42 (s, 1H), 4.89-4.76 (m, 1H), 4.55 (d, J=13.6Hz, 1H), 3.16-3.06 (m, 1H), 3.00-2.92 (m, 1H), 2.75-2.64 (m, 1H), 2.41 (s, 6H), 2.12-2.03 (m, 2H), 2.00-1.93 (m, 1H), 1.68-1.45 (m, 3H), 1.30-1.24 (m, 2H), 1.19-1.07 (m, 2H).
Embodiment 19:
2- ((3,5- dicyano -4- cyclopropyl -6- (3- methylpiperazine-1-yl) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine
Step 1:4- (the chloro- 3,5- dicyano -4- cyclopropyl pyridine -2- base of 6-) -2- methyl piperazine base -1- formic acid esters
To chloro- 4- cyclopropyl pyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in 4 step 2 of embodiment, 236mg, 2- methyl piperazine base -1- t-butyl formate 1mmol) is added in the solution in N,N-dimethylformamide (10mL) Then triethylamine (0.14mL, 1mmol) is added in (200mg, 1mmol).The mixture is stirred at room temperature 5 minutes, water is then used Dilution.The solid by filtration of precipitation is collected, dries in an oven, obtains 4- (chloro- 3, the 5- dicyano -4- cyclopropyl pyrrole of 6- Pyridine -2- base) -2- methyl piperazine base -1- formic acid esters (330mg, 82%) .LCMS m/z=301.9 [M+H-Boc]+。
Step 2:4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine - 2- yl) -2- methyl piperazine base -1- t-butyl formate
By 4- (the chloro- 3,5- dicyano -4- cyclopropyl pyridine -2- base of 6-) -2- methyl piperazine base -1- t-butyl formate The solution of (330mg, 0.82mmol) and KSAc (113mg, 0.99mmol) in n,N-Dimethylformamide (9mL) is stirred in room temperature Mix 30 minutes, then by methanesulfonic acid 2- amino -2- oxo -1- phenylethylester (in 3 step 5 of embodiment describe synthesis, 226mg, 0.99mmol) and triethylamine (0.23mL, 1.64mmol) add in the solution.The mixture was stirred at room temperature Then night is diluted with water.The solid by filtration of precipitation is collected and pass through silica gel chromatography (methylene chloride: methanol= 20:1), 4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine -2- is obtained Base) -2- methyl piperazine base -1- t-butyl formate (280mg, 64%)1H NMR (400MHz, CDCl3)δppm 7.49–7.45 (m, 2H), 7.44-7.36 (m, 3H), 6.58-6.48 (m, 1H), 5.62 (br s, 1H), 5.40-5.35 (m, 1H), 4.49- 4.27 (m, 3H), 4.03-3.95 (m, 1H), 3.62-3.53 (m, 1H), 3.43-3.27 (m, 2H), 2.16-2.08 (m, 1H), 1.50 (s, 9H), 1.35-1.28 (m, 2H), 1.27-1.22 (m, 3H), 1.21-1.11 (m, 2H).
Step 3:2- ((3,5- dicyano -4- cyclopropyl -6- (3- methylpiperazine-1-yl) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide
In room temperature, to 4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyrrole Pyridine -2- base) -2- methyl piperazine base -1- t-butyl formate (280mg, 0.53mmol) in the solution in methylene chloride (5mL) plus Enter trifluoroacetic acid (4mL).The mixture is stirred at room temperature overnight, is then concentrated in vacuo, with saturation NaHCO3It is basified simultaneously It is extracted with methylene chloride (20mL x 3).Combined organic layer in vacuo is concentrated, silica gel chromatography (dichloromethane is then passed through Alkane: methanol=20:1), obtain 2- ((3,5- dicyano -4- cyclopropyl -6- (3- methylpiperazine-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides (194.5mg, 86%) .LCMS m/z=432.8 [M+H]+。1H NMR (400MHz, CDCl3)δppm 7.48-7.42 (m, 2H), 7.41-7.31 (m, 3H), 6.53 (s, 1H), 5.82-5.72 (m, 1H), 5.34 (s, 1H), 4.58- 4.46 (m, 2H), 3.26-3.12 (m, 2H), 2.99-2.78 (m, 3H), 2.15-2.03 (m, 2H), 1.33-1.24 (m, 2H), 1.20-1.09 (m, 5H).
Embodiment 20:
2- ((3,5- dicyano -4- cyclopropyl -6- (2- (hydroxymethyl) morpholino) pyridine -2- base) sulfenyl) -2- phenyl Acetamide
The chloro- 4- cyclopropyl -6- of step 1:2- (3,5- lupetazin -1- base) pyridine -3,5- dimethoxy nitrile
To chloro- 4- cyclopropyl pyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in 4 step 2 of embodiment, 237mg, 2,6-dimethyl-piperizine (114mg, 1mmol) 1mmol) is added in the solution in n,N-Dimethylformamide (10mL), then It is added triethylamine (0.14mL, 1mmol).The mixture is stirred at room temperature 5 minutes, is then diluted with water.By the solid of precipitation It is collected by filtration and dries in an oven, obtain the chloro- 4- cyclopropyl -6- of 2- (3,5- lupetazin -1- base) pyridine -3,5- Dimethoxy nitrile (280mg, 89%), is white solid.LCMS m/z=316.0 [M+H]+。
Step 2:2- ((3,5- dicyano -4- cyclopropyl -6- (2- (hydroxymethyl) morpholino) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides
By the chloro- 4- cyclopropyl -6- of 2- (3,5- lupetazin -1- base) pyridine -3,5- dimethoxy nitrile (280mg, 0.89mmol) and the solution of KSAc (122mg, 1.07mmol) in n,N-Dimethylformamide (9mL) is stirred at room temperature 30 points Clock, then by methanesulfonic acid 2- amino -2- oxo -1- phenylethylester (describe synthesis in 3 step 5 of embodiment, 245mg, 1.07mmol) and triethylamine (0.25mL, 1.78mmol) adds to the solution.The mixture is stirred at room temperature overnight, is then used Water dilution.The solid by filtration of precipitation is collected and passes through silica gel chromatography (CH2Cl2: MeOH 10:1), obtain 2- ((3,5- dicyano -4- cyclopropyl -6- (2- (hydroxymethyl) morpholino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides (43mg, 11%), is gray solid.LCMS m/z=446.6 [M+H]+。1H NMR (400MHz, CDCl3)δppm 7.49– 7.42 (m, 2H), 7.41-7.32 (m, 3H), 6.55 (br s, 1H), 5.65 (br s, 1H), 5.34 (s, 1H), 4.61-4.49 (m, 2H), 3.10-2.75 (m, 4H), 2.12-2.04 (m, 1H), 1.37-1.18 (m, 8H), 1.18-1.11 (m, 2H).1H is not seen It measures.
Embodiment 21:
2- ((3,5- dicyano -4- cyclopropyl -6- (2,6- thebaine generation) pyridine -2- base) sulfenyl) -2- phenyl second Amide
The chloro- 4- cyclopropyl -6- of step 1:2- (2,6- thebaine generation) pyridine -3,5- dimethoxy nitrile
By chloro- 4- cyclopropyl pyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in 4 step 2 of embodiment, 238mg, 1mmol) 2,6- thebaine (115mg, 1mmol) and triethylamine (101mg, 1mmol) are at n,N-Dimethylformamide (8mL) In mixture be stirred at room temperature 30 minutes.The reaction is extracted down in water (50mL) and with ethyl acetate (50mL x 2). It by combined organic layer drying and is concentrated in vacuo, obtains the chloro- 4- cyclopropyl -6- of 2- (2,6- thebaine generation) pyridine -3,5- Dimethoxy nitrile (280mg, 89%), is white solid.LCMS m/z=317.0 [M+H]+。
Step 2:2- ((3,5- dicyano -4- cyclopropyl -6- (2,6- thebaine generation) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides
By the chloro- 4- cyclopropyl -6- of 2- (2,6- thebaine generation) pyridine -3,5- dimethoxy nitrile (280mg, 0.88mmol) and Solution of the KSAc (121mg, 1.06mmol) in n,N-Dimethylformamide (10mL) is stirred at room temperature 30 minutes, then by first Sulfonic acid 2- amino -2- oxo -1- phenylethylester (describing synthesis, 242mg, 1.06mmol in 3 step 5 of embodiment) and three Ethamine (178mg, 1.76mmol) adds to the solution.The mixture is stirred at room temperature 12 hours, is then diluted with water (50mL) And it is extracted with ethyl acetate (50mL x 2).Combined organic layer in vacuo is concentrated and passes through silica gel chromatography (CH2Cl2: MeOH 50:1), obtain 2- ((3,5- dicyano -4- cyclopropyl -6- (2,6- thebaine generation) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides (120mg, 30%), are white solid.LCMS m/z=447.8 [M+H]+。1H NMR (400MHz, CDCl3) δ ppm 7.49-7.42 (m, 2H), 7.42-7.33 (m, 3H), 6.51 (br s, 1H), 5.52 (br s, 1H), 5.31 (s, 1H), 4.56-4.45 (m, 2H), 3.75-3.60 (m, 2H), 2.94-2.81 (m, 2H), 2.14-2.04 (m, 1H), 1.36-1.22 (m, 8H), 1.18-1.12 (m, 2H).
Embodiment 22:
2- ((3,5- dicyano -4- cyclopropyl -6- (3- (dimethylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides
The chloro- 4- cyclopropyl -6- of step 1:2- (4- methyl -3- oxypiperazin -1- base) pyridine -3,5- dimethoxy nitrile
In room temperature, by chloro- 4- cyclopropyl pyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (in 4 step 2 of embodiment describe synthesis, 238mg, 1mmol) 1- methyl piperazine -2- ketone (114mg, 1mmol) and triethylamine (121mg, 1.2mmol) be in N, N- dimethyl methyl Solution in amide (8mL) stirs 30 minutes, is then diluted with water (50mL) and is extracted with ethyl acetate (50mL x 2).It will close And organic layer it is dry and be concentrated in vacuo, obtain the chloro- 4- cyclopropyl -6- of 2- (4- methyl -3- oxypiperazin -1- base) pyridine -3, 5- dimethoxy nitrile (260mg, 83%), is brown solid.LCMS m/z=315.8 [M+H]+。
Step 2:2- ((3,5- dicyano -4- cyclopropyl -6- (3- (dimethylamino) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides
By the chloro- 4- cyclopropyl -6- of 2- (4- methyl -3- oxypiperazin -1- base) pyridine -3,5- dimethoxy nitrile (260mg, 0.82mmol) and the solution of KSAc (122mg, 1.07mmol) in N,N-dimethylformamide (6mL) is stirred at room temperature 30 points Clock, then by methanesulfonic acid 2- amino -2- oxo -1- phenylethylester (describe synthesis in 3 step 5 of embodiment, 244mg, 1.07mmol) and triethylamine (166mg, 1.64mmol) adds to the solution.The mixture is stirred at room temperature 12 hours, is then used Water (50mL) dilution is simultaneously extracted with ethyl acetate (50mL x 2).Combined organic layer is dry, then vacuum concentration passes through silicon Rubber column gel column chromatogram purification (CH2Cl2: MeOH 40:1), obtain 2- ((3,5- dicyano -4- cyclopropyl -6- (3- (dimethylamino) piperazines Pyridine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides (110mg, 30%) are white solid.LCMS m/z=446.8 [M+H]+。1H NMR (400MHz, CDCl3) δ ppm 7.53-7.44 (m, 2H), 7.44-7.33 (m, 3H), 6.87 (br s, 1H), 5.76 (br s, 1H), 5.41 (s, 1H), 4.52 (d, J=17.4Hz, 1H), 4.34 (d, J=17.4Hz, 1H), 4.25-4.15 (m, 1H), 4.12-3.99 (m, 1H), 3.50 (s, 2H), 3.03 (s, 3H), 2.15-2.06 (m, 1H), 1.36-1.27 (m, 2H), 1.23-1.12 (m, 2H).
Embodiment 23:
2- ((6- (4- (amino methyl) -4- hydroxy piperidine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulphur Base) -2- phenyl-acetamides
Step 1:4- (amino methyl) -1- benzyl piepridine -4- alcohol
To the precooling solution of 1- benzyl piepridine -4- ketone (1.0g, 5.3mmol) and triethylamine (0.15mL 1.1mmol) TMS-CN (0.63g, 6.4mmol) is added in (20 DEG C).The mixture is stirred at room temperature 3 hours, it is then carefully mixed to this It closes in object and LiAlH is added4Tetrahydrofuran (50mL) solution of (0.23g, 6.1mmol).The mixture is flowed back 1.5 hours, so After be cooled to room temperature, be quenched with water (0.23mL), be then quenched with NaOH solution (1N, 0.23mL) and water (0.46mL).It should Mixture is stirred overnight, and is then filtered, which is concentrated, and obtains 4- (amino methyl) -1- benzyl piepridine -4- alcohol (1.2g).LCMS m/z=221.0 [M+H]+。
Step 2:((1- benzyl -4- hydroxy piperidine -4- base) methyl) t-butyl carbamate
To 4- (amino methyl) -1- benzyl piepridine -4- alcohol (1.2g, crude) in the solution in methylene chloride (25mL) It is added (Boc)2O (1.4g, 6.4mmol).The mixture is stirred at room temperature overnight, be then concentrated in vacuo and passes through silicagel column color (petroleum ether: ethyl acetate (2:1) obtains ((1- benzyl -4- hydroxy piperidine -4- base) methyl) t-butyl carbamate for spectrum purifying (1.2g, 71%).1H NMR (400MHz, CDCl3) δ ppm 7.38-7.31 (m, 4H), 7.28-7.24 (m, 1H), 4.92 (br S, 1H), 3.56 (s, 2H), 3.20-3.10 (m, 2H), 2.69-2.57 (m, 2H), 2.49-2.29 (m, 3H), 1.72-1.57 (m, 4H), 1.46 (s, 9H).
Step 3:((4- hydroxy piperidine -4- base) methyl) t-butyl carbamate
To ((1- benzyl -4- hydroxy piperidine -4- base) methyl) t-butyl carbamate (800mg, 2.5mmol) in ethyl alcohol Hydrazine hydrate (0.25mL, 5mmol) and Pd/C (280mg) are added in solution in (25mL).The mixture is flowed back 3 hours.It will The mixture passes throughIt filters and the filter vacuum is concentrated and passes through silica gel chromatography (CH2Cl2:MeOH 20: 1) ((4- hydroxy piperidine -4- base) methyl) t-butyl carbamate (400mg, 70%), is obtained1H NMR (400MHz, CDCl3)δ Ppm 5.08 (br s, 1H), 3.17-3.08 (m, 2H), 3.01-2.92 (m, 2H), 2.90-2.82 (m, 2H), 2.45 (br s, 2H), 1.61-1.50 (m, 4H), 1.45 (s, 9H).
Step 4:((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyrrole Pyridine -2- base) -4- hydroxy piperidine -4- base) methyl) t-butyl carbamate
To chloro- 4- cyclopropyl pyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in 4 step 2 of embodiment, 237mg, ((4- hydroxy piperidine -4- base) methyl) carbamic acid uncle 1mmol) is added in the solution in N,N-dimethylformamide (10mL) Butyl ester (230mg, 1mmol), is then added Et3N(0.14mL 1mmol).The mixture is stirred at room temperature 5 minutes, is then used Water dilution.The solid by filtration of precipitation is collected and is passed through silica gel chromatography (DCM: ethyl acetate 1:1), is obtained The residue of 300mg.By the solution of the residue and KSAc (96mg, 0.84mmol) in n,N-Dimethylformamide (7mL) It is stirred at room temperature 30 minutes, then (describes in 3 step 5 of embodiment methanesulfonic acid 2- amino -2- oxo -1- phenylethylester Synthesis, 191mg, 0.84mmol) and Et3N (0.19mL, 1.4mmol) adds to the solution.The mixture was stirred at room temperature Then night is diluted with water.The solid by filtration of precipitation is collected, silica gel chromatography (CH is then passed through2Cl2:MeOH 20:1), ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine -2- is obtained Base) -4- hydroxy piperidine -4- base) methyl) t-butyl carbamate (233mg) is yellow solid.LCMS m/z=562.8 [M +H]+。
Step 5:2- ((6- (4- (amino methyl) -4- hydroxy piperidine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- Base) sulfenyl) -2- phenyl-acetamides
In room temperature, to ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl Pyridine -2- base) -4- hydroxy piperidine -4- base) methyl) t-butyl carbamate (233mg, 0.41mmol) is at methylene chloride (4mL) In solution in be added trifluoroacetic acid (3mL).The mixture is stirred at room temperature overnight, is then concentrated in vacuo, with saturation NaHCO3It is water-soluble basified and with methylene chloride (20mL x 3) extract.Combined organic layer in vacuo is concentrated and passes through silicagel column Chromatogram purification (DCM:MeOH 10:1) obtains 2- ((6- (4- (amino methyl) -4- hydroxy piperidine -1- base) -3,5- dicyano - 4- cyclopropyl pyridine -2- base) sulfenyl) -2- phenyl-acetamides (62.2mg, 33%).LCMS m/z=462.7 [M+H]+。1H NMR (400MHz, CD3OD) δ ppm 7.54 (d, J=6.8Hz, 2H), 7.44-7.35 (m, 3H), 5.51 (s, 1H), 4.44 (dd, J= 17.5,14.3Hz, 2H), 3.56 (dd, J=24.0,10.7Hz, 2H), 2.63 (s, 2H), 2.17-2.07 (m, 1H), 1.77- 1.60 (m, 4H), 1.27-1.20 (m, 2H), 1.11-1.05 (m, 2H).5H is not observed.
Embodiment 24
2- ((3,5- dicyano -4- cyclopropyl -6- (3- (methylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide
Step 1:1- Benzyl-N-methyl piperidines -3- amine
The four of methylamine is added in the solution in methylene chloride (25mL) to 1- benzyl piepridine -3- ketone (1.0g, 5.3mmol) Hydrogen tetrahydrofuran solution (5.3mL, 2M, 10.6mmol).The mixture is stirred at room temperature 5 minutes, then by NaBH (OAc)3 (2.2g, 10.6mmol) adds to the solution.The mixture is stirred at room temperature overnight, then with saturation NaHCO3Aqueous solution is washed It washs, drying is simultaneously concentrated in vacuo, and obtains 1- Benzyl-N-methyl piperidines -3- amine (1.0g, crude).LCMS m/z=205.1 [M+ H]+。
Step 2:(1- benzyl piepridine -3- base) (methyl) t-butyl carbamate
To 1- Benzyl-N-methyl piperidines -3- amine (1.0g) and triethylamine (1.36mL, 9.8mmol) in methylene chloride (Boc) is added in solution in (25mL)2O (1.26g, 5.9mmol).The mixture is stirred at room temperature overnight, then vacuum It is concentrated and passes through silica gel chromatography (petroleum ether: ethyl acetate 4:1), obtain (1- benzyl piepridine -3- base) (methyl) amino T-butyl formate (1.3g) .LCMS m/z=305.0 [M+H]+。
Step 3:(1- (the chloro- 3,5- dicyano -4- cyclopropyl pyridine -2- base of 6-) piperidines -3- base) (methyl) carbamic acid The tert-butyl ester
To ((1- benzyl -4- hydroxy piperidine -4- base) methyl) t-butyl carbamate (1.3g, 4.3mmol) in methanol Pd/C (130mg) is added in solution in (20mL).By the mixture in room temperature H2It is stirred overnight under atmosphere (1 atmospheric pressure), Then it filters.The filter vacuum is concentrated, crude methyl (piperidines -3- base) t-butyl carbamate is obtained, is residue. Exist to chloro- 4- cyclopropyl pyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describing synthesis, 236mg, 1mmol in 4 step 2 of embodiment) Methyl (piperidines -3- base) is added in solution in N,N-dimethylformamide (10mL), and (214mg's is crude for t-butyl carbamate Above-mentioned residue), then be added triethylamine (0.14mL 1mmol).The mixture is stirred at room temperature 5 minutes, water is then used Dilution.The solid by filtration of precipitation is collected and is passed through silica gel chromatography (methylene chloride: ethyl acetate 1:1), is obtained (1- (chloro- 3, the 5- dicyano -4- cyclopropyl pyridine -2- base of 6-) piperidines -3- base) (methyl) t-butyl carbamate (320mg, 77%).LCMS m/z=315.8 [M+H-Boc]+。
Step 4:(1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine - 2- yl) piperidines -3- base) (methyl) t-butyl carbamate
By (1- (the chloro- 3,5- dicyano -4- cyclopropyl pyridine -2- base of 6-) piperidines -3- base) tertiary fourth of (methyl) carbamic acid The solution of ester (320mg, 0.77mmol) and KSAc (106mg, 0.93mmol) in n,N-Dimethylformamide (8mL) is in room temperature Stirring 30 minutes, then by methanesulfonic acid 2- amino -2- oxo -1- phenylethylester (in 3 step 5 of embodiment describe synthesis, 212mg, 0.93mmol) and triethylamine (0.21mL, 1.54mmol) add to the solution.The mixture is stirred at room temperature overnight, Then it is diluted with water.The solid by filtration of precipitation is collected and is passed through silica gel chromatography (methylene chloride: methanol 20:1), Obtain (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine -2- base) piperidines - 3- yl) (methyl) t-butyl carbamate (250mg, 60%).LCMS m/z=446.8 [M+H-Boc]+。
Step 5:2- ((3,5- dicyano -4- cyclopropyl -6- (3- (methylamino) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides
To (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine -2- Base) piperidines -3- base) solution addition trifluoro second of (methyl) t-butyl carbamate (250mg, 0.46mmol) in DCM (5mL) Sour (3mL).The mixture is stirred at room temperature overnight, is then concentrated in vacuo, with saturation NaHCO3It is water-soluble basified and extracted with DCM It takes.Organic layer in vacuo is concentrated and is passed through silica gel chromatography (DCM:MeOH 20:1), 2- ((3,5- dicyano -4- are obtained Cyclopropyl -6- (3- (methylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- phenyl-acetamides (180mg, 88%).LCMS M/z=446.7 [M+H]+。1H NMR (400MHz, CD3OD) δ ppm 7.48-7.42 (m, 2H), 7.36-7.26 (m, 3H), 5.45 (s, 1H), 4.54-4.45 (m, 1H), 4.41-4.27 (m, 1H), 3.19-3.11 (m, 1H), 3.02-2.93 (m, 1H), 2.72- 2.60 (m, 1H), 2.41 (d, J=5.6Hz, 3H), 2.11-2.01 (m, 2H), 1.87-1.78 (m, 1H), 1.65-1.52 (m, 1H), 1.42-1.31 (m, 1H), 1.19-1.11 (m, 2H), 1.05-0.94 (m, 2H).3H is not observed.
Embodiment 25
2- ((6- (3- amino piperidine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- phenylacetyl Amine
Step 1:(1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine - 2- yl) piperidines -3- base) t-butyl carbamate
To chloro- 4- cyclopropyl pyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in 4 step 2 of embodiment, 236mg, 1mmol) in the solution in n,N-Dimethylformamide (10mL) be added piperidines -3- carbamate (200mg, 1mmol) and triethylamine (0.14mL, 1mmol).The mixture is stirred at room temperature 5 minutes.Water is added in the reaction and by institute Mixture filtering is obtained, crude solid is obtained.By crude solid (401mg) and KSAc (137mg, 1.2mmol) in N, N- dimethyl Solution in formamide (10mL) is stirred at room temperature 30 minutes.Then by methanesulfonic acid 2- amino -2- oxo -1- phenylethylester (describing synthesis, 275mg, 1.2mmol in 3 step 5 of embodiment) and triethylamine (0.28mL, 2mmol) add to the reaction.It will Acquired solution is stirred at room temperature overnight.Water is added in the reaction.The solid is filtered and uses flash column chromatography (dichloromethane Alkane: ethyl acetate 1:1), obtain (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl Yl pyridines -2- base) piperidines -3- base) t-butyl carbamate (230mg, 43%).LCMS m/z=554.8 [M+Na]+。
Step 2:2- ((6- (3- amino piperidine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- benzene Yl acetamide
To (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine -2- Base) piperidines -3- base) trifluoro second is added in t-butyl carbamate (230mg, 0.43mL) in the solution in methylene chloride (4mL) Sour (4mL).The reaction is stirred at room temperature overnight.Acquired solution is concentrated and uses saturation NaHCO3Aqueous solution neutralizes, and uses dichloro Methane extraction, organic layer is washed with brine, and is concentrated and (is eluted with DCM:MeOH 10:1) with flash column chromatography, is obtained 2- ((6- (3- amino piperidine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- phenyl-acetamides (180.5mg, 92%).LCMS m/z=432.7 [M+H]+。1H NMR (400MHz, CD3OD) δ ppm 7.55 (d, J=7.0Hz, 2H), 7.45-7.35 (m, 3H), 5.50 (d, J=6.4Hz, 1H), 4.61-4.47 (m, 1H), 4.46-4.38 (m, 1H), 3.31- 3.23 (m, 1H), 3.07-2.84 (m, 2H), 2.18-2.03 (m, 2H), 1.94-1.85 (m, 1H), 1.73-1.60 (m, 1H), 1.52-1.41 (m, 1H), 1.28-1.20 (m, 2H), 1.15-1.04 (m, 2H).4H is not observed.
Embodiment 26:
2- ((3,5- dicyano -4- cyclopropyl -6- (dimethylamino) pyridine -2- base) sulfenyl) -2- (pyridin-4-yl) second Amide
Chloro- 4- cyclopropyl -6- (dimethylamino) pyridine -3,5- dimethoxy nitrile of step 1:2-
To chloro- 4- cyclopropyl pyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in 4 step 2 of embodiment, 4.8g, 20.3mmol) in the solution in n,N-Dimethylformamide (100mL) be added dimethylamine (tetrahydrofuran solution of 2M, 10mL, 20.3mmol) and triethylamine (2.8mL, 20.3mmol).The reaction is stirred at room temperature 5 minutes.Water is added in the reaction.It will The solid filters and is washed with water and is dried to obtain chloro- 4- cyclopropyl -6- (dimethylamino) pyridine -3,5- dimethoxy nitrile of 2- (4.6g, 92%), is pink solid.LCMS m/z=246.9 [M+H]+。
Step 2:2- ((3,5- dicyano -4- cyclopropyl -6- (dimethylamino) pyridine -2- base) sulfenyl) -2- (pyridine - 4- yl) acetamide
By chloro- 4- cyclopropyl -6- (dimethylamino) pyridine -3, the 5- dimethoxy nitrile (400mg, 1.62mL) of 2-, KSAc The mixture of (221mg, 1.94mmol) in n,N-Dimethylformamide (10mL) is stirred at room temperature 30 minutes.Then first is added Sulfonic acid 2- amino -2- oxo -1- (pyridin-4-yl) ethyl ester (describe synthesis in 9 step 3 of embodiment, 448mg, 1.94mmol)、Et3N (327mg, 3.24mmol).Gained mixture is stirred at room temperature 12 hours.The reaction mixture is fallen It is extracted into water (50mL) and with ethyl acetate (50mL x 2).Combined organic layer is dried and concentrated.The residue is used Silica gel column purification is eluted with methylene chloride/methanol (60/1), obtains 2- ((3,5- dicyano -4- cyclopropyl -6- (dimethylaminos Base) pyridine -2- base) sulfenyl) -2- (pyridin-4-yl) acetamide (220mg, 36% yield) is white solid.LCMS m/z =378.9 [M+H]+。1H NMR (400MHz, DMSO) δ ppm 8.57 (d, J=4.9Hz, 2H), 8.07 (s, 1H), 7.53 (d, J =4.9Hz, 2H), 7.49 (s, 1H), 5.65 (s, 1H), 3.27 (s, 6H), 2.15-2.03 (m, 1H), 1.19-1.08 (m, 2H), 0.98-0.88 (m, 2H).
Embodiment 27:
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (pyridin-4-yl) acetyl Amine
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (pyridin-4-yl) acetyl Amine
2- chloro- 6- (dimethylamino) -4- ethylpyridine -3,5- dimethoxy nitrile (in 3 step 3 of embodiment is described into conjunction At the mixture of 234.7mg, 1mmol), KSAc (137mg, 1.2mmol) in n,N-Dimethylformamide (10mL) in room temperature Stirring 30 minutes.Then methanesulfonic acid 2- amino -2- oxo -1- (pyridin-4-yl) ethyl ester is added (to describe in 9 step 3 of embodiment Synthesis, 276mg, 1.2mmol) triethylamine (202mg, 20mmol).Gained mixture is stirred at room temperature 12 hours.This is anti- Mixture is answered to extract down in water (50mL) and with ethyl acetate (50mL x 2).Combined organic layer is dried and concentrated.It will Residue silica gel column purification, with methylene chloride: methanol 40:1 is eluted, and obtains 2- ((3,5- dicyano -6- (dimethylaminos Base) -4- ethylpyridine -2- base) sulfenyl) -2- (pyridin-4-yl) acetamide (120mg, 33% yield) is white solid. LCMS m/z=366.9 [M+H]+。1H NMR (400MHz, DMSO) δ ppm 8.57 (dd, J=4.5,1.5Hz, 2H), 8.07 (br S, 1H), 7.53 (dd, J=4.5,1.5Hz, 2H), 7.49 (br s, 1H), 5.66 (s, 1H), 3.30 (s, 6H), 2.75 (q, J= 7.5Hz, 2H), 1.20 (t, J=7.6Hz, 3H).
Embodiment 28:
2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- phenylacetyl Amine
Step 1:(1- (the chloro- 3,5- dicyano -4- cyclopropyl pyridine -2- base of 6-) piperidin-4-yl) t-butyl carbamate
To chloro- 4- cyclopropyl pyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in 4 step 2 of embodiment, 236mg, 1mmol) in the solution in n,N-Dimethylformamide (10mL) be added piperidin-4-yl t-butyl carbamate (200mg, 1mmol) and triethylamine (0.14mL, 1mmol).The mixture is stirred at room temperature 5 minutes.Water is added in the reaction.It should Solid is filtered and is dried, and obtains (1- (chloro- 3, the 5- dicyano -4- cyclopropyl pyridine -2- base of 6-) piperidin-4-yl) carbamic acid uncle Butyl ester (390mg, 97%).LCMS m/z=423.7 [M+Na]+。
Step 2:(1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine - 2- yl) piperidin-4-yl) t-butyl carbamate
To methanesulfonic acid 2- amino -2- oxo -1- phenylethylester (describe synthesis in 3 step 5 of embodiment, 390mg, KSAc (133mg, 117mmol) 0.97mmol) is added in the solution in n,N-Dimethylformamide (10mL).The reaction is existed It is stirred at room temperature 30 minutes, then by (1- (6- chloro- 3,5- dicyano -4- cyclopropyl pyridine -2- base) piperidin-4-yl) carbamic acid The tert-butyl ester (267mg, 1.17mmol) and triethylamine (0.27mL, 1.94mmol) add to the reaction.The reaction is stirred at room temperature Overnight.Water is added in the reaction, which is filtered and (is eluted with DCM:MeOH=20:1) with flash column chromatography, is obtained To (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine -2- base) piperidines -4- Base) t-butyl carbamate (36mg).LCMS m/z=476.7 [M+H-isobutene]+(main), 554.7 [M+Na]+(secondary).
Step 3:2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- Phenyl-acetamides
By (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine -2- Base) piperidin-4-yl) trifluoroacetic acid is added in the mixture in DCM (7mL) in t-butyl carbamate (360mg, 0.68mmol) (4mL).The reaction is stirred at room temperature overnight.The solvent is removed and the residue is saturated NaHCO3Aqueous solution neutralizes simultaneously It is extracted with DCM.Organic layer is concentrated and (is eluted with DCM:MeOH=10:1) with flash column chromatography, product is obtained (200mg, 68%).LCMS m/z=432.8 [M+H]+。1H NMR (400MHz, CDCl3) δ ppm7.48-7.42 (m, 2H), 7.41-7.32 (m, 3H), 6.54 (br s, 1H), 5.75 (br s, 1H), 5.35 (s, 1H), 4.57-4.46 (m, 2H), 3.30- 3.19 (m, 2H), 3.10-3.00 (m, 1H), 2.12-2.04 (m, 1H), 2.04-1.94 (m, 2H), 1.79 (br s, 2H), 1.52-1.39 (m, 2H), 1.33-1.24 (m, 2H), 1.18-1.11 (m, 2H).
Embodiment 29:
2- ((3,5- dicyano -4- cyclopropyl -6- (4- (dimethylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides
The chloro- 4- cyclopropyl -6- of step 1:2- (4- (dimethylamino) piperidin-1-yl) pyridine -3,5- dimethoxy nitrile
To chloro- 4- cyclopropyl pyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in 4 step 2 of embodiment, 200mg, 0.85mmol) it is added N in the solution in n,N-Dimethylformamide (9mL), N- lupetidine -4- amine (108mg, 0.85mmol) and triethylamine (0.12mL, 0.85mmol).The mixture is stirred at room temperature 5 minutes.Water is added into the reaction In.The solid is filtered and is dried to obtain the chloro- 4- cyclopropyl -6- of 2- (4- (dimethylamino) piperidin-1-yl) pyridine -3,5- two Formonitrile HCN (210mg, 75% yield).LCMS m/z=330.3 [M+H]+。
Step 2:2- ((3,5- dicyano -4- cyclopropyl -6- (4- (dimethylamino) piperidin-1-yl) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides
By the chloro- 4- cyclopropyl -6- of 2- (4- (dimethylamino) piperidin-1-yl) pyridine -3,5- dimethoxy nitrile (210mg, 0.64mmol) and the solution of KSAc (88mg, 0.77mmol) in n,N-Dimethylformamide (7mL) is stirred at room temperature 30 points Clock.By methanesulfonic acid 2- amino -2- oxo -1- phenylethylester (describe synthesis in 3 step 5 of embodiment, 176mg, 0.77mmol) added in the reaction with triethylamine (0.81mL, 1.28mmol).The mixture is stirred at room temperature overnight.By water Add in the reaction, which is filtered and (eluted with DCM:MeOH=20:1) with flash column chromatography, obtain 2- ((3, 5- dicyano -4- cyclopropyl -6- (4- (dimethylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- phenyl-acetamides (180mg, 61% yield).LCMS m/z=460.9 [M+H]+。1H NMR (400MHz, CDCl3) δ ppm 7.50-7.45 (m, 2H), 7.44-7.35 (m, 3H), 6.54 (br s, 1H), 5.57 (br s, 1H), 5.39 (s, 1H), 4.69-4.62 (m, 2H), 3.19 (t, J=12.6Hz, 2H), 2.52-2.43 (m, 1H), 2.36 (s, 6H), 2.14-2.01 (m, 3H), 1.65-1.58 (m, 2H), 1.34-1.27 (m, 2H), 1.20-1.13 (m, 2H).
Embodiment 30:
2- ((3,5- dicyano -4- cyclopropyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- (pyridin-4-yl) second Amide
Step 1:4- (the chloro- 3,5- dicyano -4- cyclopropyl pyridine -2- base of 6-) piperazinyl -1- t-butyl formate
By chloro- 4- cyclopropyl pyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in 4 step 2 of embodiment, 1.0g, 4.2mmol), piperazinyl -1- t-butyl formate (782mg, 4.2mmol) and Et3N (424mg, 1.2mmol) is in N, N- dimethyl Mixture in formamide (20mL) is stirred at room temperature 30 minutes.By the reaction mixture down in water (100mL) and using EtOAc (100mL x 2) extraction.Combined organic layer is dried and concentrated, 4- (chloro- 3, the 5- dicyano -4- cyclopropyl pyridine-of 6- is obtained 2- yl) piperazinyl -1- t-butyl formate (1.3g, 80%) is white solid.LCMS m/z=288.0 [M+H-Boc]+。
Step 2:4- (6- ((2- amino -2- oxo -1- (pyridin-4-yl) ethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl Yl pyridines -2- base) piperazinyl -1- t-butyl formate
By 4- (chloro- 3, the 5- dicyano -4- cyclopropyl pyridine -2- base of 6-) piperazinyl -1- t-butyl formate (400mg, 1.03mmol) stirred with the solution of thioacetic acid potassium (142mg, 1.24mmol) in n,N-Dimethylformamide (10mL) in room temperature It mixes 30 minutes, methanesulfonic acid 2- amino -2- oxo -1- (pyridin-4-yl) ethyl ester (in 9 step 3 of embodiment is then described into conjunction At 285mg, 1.24mmol) and Et3N (208mg, 2.06mmol) adds to the reaction.It is small that the mixture is stirred at room temperature 12 When, it is subsequently poured into water (50mL) and is extracted with EtOAc (50mL x 2).Combined organic layer is dried and concentrated.It will be remaining Residue passes through silica gel chromatography (MeOH:CH2Cl21:70), 4- (6- ((2- amino -2- oxo -1- (pyridine -4- is obtained Base) ethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine -2- base) piperazinyl -1- t-butyl formate (380mg, 71%), For white solid.LCMS m/z=519.9 [M+H]+。
Step 3:2- ((3,5- dicyano -4- cyclopropyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- (pyridine - 4- yl) acetamide
By 4- (6- ((2- amino -2- oxo -1- (pyridin-4-yl) ethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyrrole Pyridine -2- base) piperazinyl -1- t-butyl formate (5) (380mg, 0.73mmol) and trifluoroacetic acid (2mL) be at methylene chloride (8mL) In mixture be stirred at room temperature 12 hours.After reaction mixture concentration, by remaining residue down in water (50mL), Use NaHCO3Solution carries out alkalization and is extracted with methylene chloride (50mL x 2).Combined organic layer is dried and concentrated.It will remain Remaining residue obtains 2- ((3,5- dicyano -4- cyclopropyl -6- (piperazines by silica gel chromatography (MeOH:DCM 1:30) Piperazine -1- base) pyridine -2- base) sulfenyl) -2- (pyridin-4-yl) acetamide (110mg, 36%) is white solid.LCMS m/z =442.0 [M+Na]+。1H NMR (400MHz, DMSO) δ ppm 8.57 (d, J=5.3Hz, 2H), 8.09 (br s, 1H), 7.60- 7.42 (m, 3H), 5.59 (s, 1H), 3.81-3.65 (m, 4H), 3.34 (br s, 1H), 2.89-2.68 (m, 4H), 2.19-2.04 (m, 1H), 1.18-1.07 (m, 2H), 1.00-0.93 (m, 2H).
Embodiment 31:
2- ((3,5- dicyano -4- cyclopropyl -6- (1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (pyridin-4-yl) acetamide
Step 1:4- (6- ((2- amino -2- oxo -1- (pyridin-4-yl) ethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl Yl pyridines -2- base) -1,4- Diazesuberane -1- t-butyl formate
By the tertiary fourth of 4- (the chloro- 3,5- dicyano -4- cyclopropyl pyridine -2- base of 6-) -1,4- Diazesuberane -1- formic acid Ester (describing synthesis, 402mg, 1.0mmol in 4 step 3 of embodiment) and thioacetic acid potassium (137mg, 1.2mmol) are in N, N- Mixture in dimethylformamide (10mL) is stirred at room temperature 30 minutes, then by methanesulfonic acid 2- amino -2- oxo -1- (pyrrole Pyridine -4- base) ethyl ester (describing synthesis, 345mg, 1.5mmol in 9 step 3 of embodiment) and Et3N (202mg, 2.0mmol) adds To the reaction.The mixture is stirred at room temperature 12 hours, is subsequently poured into water (50mL) and with ethyl acetate (50mL x 2) Extraction.Combined organic layer is dried and concentrated.Remaining residue is passed through into silica gel chromatography (MeOH:CH2Cl2 1: 80) 4- (6- ((2- amino -2- oxo -1- (pyridin-4-yl) ethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine -, is obtained 2- yl)-Isosorbide-5-Nitrae-Diazesuberane -1- t-butyl formate (380mg, 71%) is brown solid.LCMS m/z=533.9 [M+H]+。
Step 2:2- ((3,5- dicyano -4- cyclopropyl -6- (1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (pyridin-4-yl) acetamide
By 4- (6- ((2- amino -2- oxo -1- (pyridin-4-yl) ethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyrrole Pyridine -2- base)-Isosorbide-5-Nitrae-Diazesuberane -1- t-butyl formate (380mg, 0.71mmol) and trifluoroacetic acid (2mL) be in dichloromethane Mixture in alkane (10mL) is stirred at room temperature 12 hours.After reaction mixture concentration, by remaining residue down to water In (50mL), NaHCO is used3Solution carries out alkalization and is extracted with methylene chloride (50mL x 2).Combined organic layer is dry simultaneously Concentration.By remaining residue by silica gel chromatography (MeOH:DCM 1:30), 2- ((3,5- dicyano -4- rings are obtained Propyl -6- (Isosorbide-5-Nitrae-Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (pyridin-4-yl) acetamide (120mg, It 40%), is white solid.LCMS m/z=433.9 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.58 (d, J= 5.6Hz, 2H), 8.10 (br s, 1H), 7.55-7.47 (m, 3H), 5.56 (s, 1H), 3.92-3.75 (m, 4H), 3.33 (br s, 1H), 2.98-2.84 (m, 2H), 2.80-2.73 (m, 2H), 2.15-2.07 (m, 1H), 1.85-1.70 (m, 2H), 1.18-1.09 (m, 2H), 0.98-0.92 (m, 2H).
Embodiment 32:
2- ((3,5- dicyano -4- cyclopropyl -6- ((R) -3- hydroxy piperidine -1- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide
Step 1:(R) the chloro- 4- cyclopropyl -6- of -2- (3- hydroxy piperidine -1- base) pyridine -3,5- dimethoxy nitrile
To chloro- 4- cyclopropyl pyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in 4 step 2 of embodiment, 237mg, 0.995mmol) in the solution in n,N-Dimethylformamide (10mL) be added (R)-piperidin-3-ol (101mg, 0.995mmol) and Et3N (0.139mL, 0.995mmol).The reaction mixture is stirred overnight at 25 DEG C.By the reaction water After dilution, the solid by filtration of precipitation is collected and is dried in an oven, chloro- 4- cyclopropyl -6- (the 3- hydroxyl of (R) -2- is obtained Piperidin-1-yl) pyridine -3,5- dimethoxy nitrile (275mg, 91%).LCMS m/z=303.1 [M+H]+。
Step 2:2- ((3,5- dicyano -4- cyclopropyl -6- ((R) -3- hydroxy piperidine -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides
By the chloro- 4- cyclopropyl -6- of (R) -2- (3- hydroxy piperidine -1- base) pyridine -3,5- dimethoxy nitrile (275mg, 0.908mmol) stirred with the solution of thioacetic acid potassium (124mg, 1.09mmol) in n,N-Dimethylformamide (8mL) in room temperature It mixes 30 minutes.Then triethylamine (0.253mL, 1.817mmol) and methanesulfonic acid 2- amino -2- oxo -1- phenylethylester is added (describing synthesis, 250mg, 1.09mmol in 3 step 5 of embodiment) and the reaction mixture is stirred overnight at 25 DEG C.It will After the reaction is diluted with water, the solid by filtration of precipitation is collected and is passed through silica gel chromatography (MeOH:DCM 1:20), Obtain 2- ((3,5- dicyano -4- cyclopropyl -6- ((R) -3- hydroxy piperidine -1- base) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine (80mg, 20%) .LCMS m/z=434.2 [M+H]+。1H NMR (400MHz, CDCl3) δ ppm 7.52-7.43 (m, 2H), 7.43-7.32 (m, 3H), 6.93-6.79 (m, 1H), 5.83-5.68 (m, 1H), 5.28-5.20 (m, 1H), 4.65-4.44 (m, 1H), 4.05-3.98 (m, 0.5H), 3.94-3.87 (m, 1.5H), 3.81-3.75 (m, 0.5H), 3.66-3.55 (m, 0.5H), 3.48-3.38 (m, 0.5H), 3.07-2.99 (m, 0.5H), 2.29 (br s, 1H), 2.12-1.89 (m, 3H), 1.78-1.48 (m, 2H), 1.34-1.23 (m, 2H), 1.20-1.08 (m, 2H).
Embodiment 33:
2- (3,5- dicyano -4- cyclopropyl -6- ((S) -3- hydroxy piperidine -1- base) pyridine -2- base sulfenyl) -2- phenyl Acetamide
Step 1:(S) the chloro- 4- cyclopropyl -6- of -2- (3- hydroxy piperidine -1- base) pyridine -3,5- dimethoxy nitrile
To chloro- 4- cyclopropyl pyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in 4 step 2 of embodiment, 237mg, 0.995mmol) in the solution in n,N-Dimethylformamide (10mL) be added (S)-piperidin-3-ol (101mg, 0.995mmol) and triethylamine (0.139mL, 0.995mmol).The reaction mixture is stirred overnight at 25 DEG C.The reaction is used After water dilution, the solid by filtration of precipitation is collected and is dried to obtain the chloro- 4- cyclopropyl -6- of (S) -2- (3- hydroxy piperidine -1- Base) pyridine -3,5- dimethoxy nitrile (275mg, 91%) .LCMS m/z=303.1 [M+H]+。
Step 2:2- (3,5- dicyano -4- cyclopropyl -6- ((S) -3- hydroxy piperidine -1- base) pyridine -2- base sulfenyl) - 2- phenyl-acetamides
By the chloro- 4- cyclopropyl -6- of (S) -2- (3- hydroxy piperidine -1- base) pyridine -3,5- dimethoxy nitrile (275mg, 0.908mmol) stirred with the solution of thioacetic acid potassium (124mg, 1.09mmol) in n,N-Dimethylformamide (8mL) in room temperature It mixes 30 minutes.Then triethylamine (0.253mL, 1.817mmol) and methanesulfonic acid 2- amino -2- oxo -1- phenylethylester is added (describing synthesis, 250mg, 1.09mmol in 3 step 5 of embodiment) and the reaction mixture is stirred overnight at 25 DEG C.It will After the reaction is diluted with water, the solid by filtration of precipitation is collected and is passed through silica gel chromatography (MeOH:DCM 1:20), Obtain 2- (3,5- dicyano -4- cyclopropyl -6- ((S) -3- hydroxy piperidine -1- base) pyridine -2- base sulfenyl) -2- phenyl-acetamides (110mg, 28%) .LCMS m/z=434.1 [M+H]+。1H NMR (400MHz, CDCl3) δ ppm 7.50-7.43 (m, 2H), 7.42-7.34 (m, 3H), 6.92-6.79 (m, 1H), 5.77-5.64 (m, 1H), 5.28-5.21 (m, 1H), 4.63-4.46 (m, 1H), 4.05-3.98 (m, 0.5H), 3.95-3.88 (m, 1.5H), 3.81-3.75 (m, 0.5H), 3.65-3.56 (m, 0.5H), 3.49-3.39 (m, 0.5H), 3.07-2.99 (m, 0.5H), 2.12-2.03 (m, 2H), 2.00-1.88 (m, 2H), 1.79-1.54 (m, 2H), 1.32-1.24 (m, 2H), 1.20-1.08 (m, 2H).
Embodiment 34:
2- ((3,5- dicyano -4- cyclopropyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (pyridin-4-yl) acetamide
Step 1:(S) the chloro- 4- cyclopropyl -6- of -2- (3- hydroxyl pyrrolidine -1- base) pyridine -3,5- dimethoxy nitrile
By chloro- 4- cyclopropyl pyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in 4 step 2 of embodiment, 400mg, 1.68mmol), (S)-pyrrolidines -3- alcohol (146mg, 1.68mmol) and triethylamine (170mg, 1.68mmol) are in N, N- dimethyl Mixture in formamide (10mL) is stirred at room temperature 30 minutes.By the reaction mixture down in water (50mL) and using EtOAc (50mL x 2) extraction.Combined organic layer is dried and concentrated.Remaining residue is passed through into silica gel chromatography (MeOH:CH2Cl21:80), the chloro- 4- cyclopropyl -6- of (S) -2- (3- hydroxyl pyrrolidine -1- base) pyridine -3,5- dimethoxy nitrile is obtained (320mg, 66%), is white solid.LCMS m/z=288.9 [M+H]+。
Step 2:2- ((3,5- dicyano -4- cyclopropyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulphur Base) -2- (pyridin-4-yl) acetamide
By the chloro- 4- cyclopropyl -6- of (S) -2- (3- hydroxyl pyrrolidine -1- base) pyridine -3,5- dimethoxy nitrile (320mg, 1.11mmol) stirred with the solution of thioacetic acid potassium (152mg, 1.33mmol) in n,N-Dimethylformamide (10mL) in room temperature It mixes 30 minutes, methanesulfonic acid 2- amino -2- oxo -1- (pyridin-4-yl) ethyl ester (in 3 step 5 of embodiment is then described into conjunction At 306mg, 1.33mmol) and Et3N (224mg, 2.22mmol) is added in the reaction.It is small that the mixture is stirred at room temperature 12 When, it is subsequently poured into water (50mL) and is extracted with EtOAc (50mL x 2).Combined organic layer is dried and concentrated.It will be remaining Residue passes through silica gel chromatography (MeOH:CH2Cl21:40), 2- ((3,5- dicyano -4- cyclopropyl -6- ((S)-are obtained 3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (pyridin-4-yl) acetamide (180mg, 38%), it is solid for white Body.LCMS m/z=420.8 [M+H]+。1H NMR (400MHz, CD3OD) δ ppm 8.57 (d, J=5.1Hz, 2H), 7.63 (d, J =5.6Hz, 2H), 5.70 (s, 1H), 4.53 (s, 1H), 4.10-3.72 (m, 4H), 2.16-2.02 (m, 3H), 1.27-1.18 (m, 2H), 1.12-1.00 (m, 2H).3H is not observed.
Embodiment 35:
2- ((3,5- dicyano -4- ethyl -6- (4- ethyl piperazidine -1- base) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine
By 2- [(the bromo- 3,5- dicyano -4- ethyl -2- pyridyl group of 6-) sulfanyl] -2- phenvl-acetamide (in embodiment Synthesis, 16mg, 0.04mmol are described in 6 steps 1) solution in tetrahydrofuran (1mL) with 1- ethyl piperazidine (0.011mL, It 0.089mmol) handles and is stirred at room temperature 16 hours.By the reaction mixture dry method loading to SiO2(0.9g) and with silica gel color Spectrum purifying (4g RediSep column；0-10%MeOH, 0-1%NH3/CH2Cl2), obtain 2- [[3,5- dicyano -4- ethyl -6- (4- ethyl piperazidine -1- base) -2- pyridyl group] sulfanyl] -2- phenvl-acetamide (14mg, 81%) is white solid.LCMS M/z=435 [M+H]+。1H NMR (300MHz, DMSO-d6) δ ppm 7.92 (s, 1H), 7.52 (br d, J=6.9Hz, 2H), (7.46-7.29 m, 4H), 5.53 (s, 1H), 3.37-3.30 (m, 4H), 2.84-2.54 (m, 2H), 2.48-2.32 (m, 6H), 1.20 (t, J=7.6Hz, 3H), 1.04 (t, J=7.1Hz, 3H).
Embodiment 36:
2- ((3,5- dicyano -4- ethyl -6- (1- oxa- -6- azaspiro [3.4] octyl- 6- yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides
Step 1:3- hydroxypyrrole alkyl -1- benzyl formate
Chloro-carbonic acid is added in the solution in methylene chloride (300mL) to pyrrolidines -3- alcohol (10.45g, 120.1mmol) Benzyl ester (24.6g, 144mmol) and triethylamine (24.3g, 240.2mmol).Acquired solution is stirred at room temperature 12 hours.It is dense It contracts after the reaction, surplus materials is allocated between ethyl acetate (100mL) and water (60mL).Separate each layer.Organic layer is used Water (60mL), saturated sodium-chloride water solution (60mL) washing, are dried and concentrated.The residue is passed through into silica gel chromatography (petroleum ether: ethyl acetate 2:1) obtains 3- hydroxypyrrole alkyl -1- benzyl formate (15.2g, 57%), for no coloring agent. LCMS m/z=222.1 [M+H]+。
Step 2:3- oxo-pyrrolidine base -1- benzyl formate
By 3- hydroxypyrrole alkyl -1- benzyl formate (14g, 63.3mmol) and IBX (21.3g, 76mmol) in acetonitrile Mixture in (200mL) stirs 2 hours at 70 DEG C.The mixture is filtered and the filtrate is concentrated.By remaining residue By silica gel chromatography (petroleum ether: ethyl acetate 1:1), obtain 3- oxo-pyrrolidine base -1- benzyl formate (11g, It 79%), is colorless oil.1H NMR (400MHz, DMSO-d6) δ ppm 7.46-7.25 (m, 5H), 5.13 (s, 2H), 3.83- 3.64 (m, 4H), 2.57 (s, 2H).
Step 3:1- oxa- -6- azaspiro [3.4] octane -6- benzyl formate
The tert-butyl alcohol is added in the solution in the tert-butyl alcohol (78mL) to Trimethylsulfoxonium Iodide (25.86g, 117.5mmol) Potassium (11.6g, 103.4mmol).The mixture is stirred 1 hour at 50 DEG C, 3- oxo-pyrrolidine base -1- formic acid benzyl is then added Ester (10.3g, 47mmol).The mixture is stirred for 48 hours at 50 DEG C.By the reaction with saturated ammonium chloride solution (200mL) It is quenched and ethyl acetate (50mL x 3) is used to extract.Combined organic layer is washed with saturated sodium chloride solution (100mL), it is dry And it is concentrated.By remaining residue by silica gel chromatography (petroleum ether: ethyl acetate 3:1), 1- oxa- -6- azepine is obtained Spiral shell [3.4] octane -6- benzyl formate (1.5g, 12%), is light yellow oil.LCMS m/z=248.0 [M+H]+。
Step 4:1- oxa- -6- azaspiro [3.4] octane
1- oxa- -6- azaspiro [3.4] octane -6- benzyl formate (1g, 4mmol) and 10% palladium/carbon (100mg) are existed Mixture in methanol (20mL) stirs 12 hours under room temperature nitrogen atmosphere.The mixture is filtered and the filtrate is concentrated.It will It is pungent to obtain 1- oxa- -6- azaspiro [3.4] by silica gel chromatography (methylene chloride: methanol 20:1) for remaining residue Alkane (700mg, crude), is colorless oil.LCMS m/z=114.0 [M+H]+。
The chloro- 4- ethyl -6- of step 5:2- (1- oxa- -6- azaspiro [3.4] octyl- 6- yl) pyridine -3,5- dimethoxy nitrile
To chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile (678mg, 3.01mmol) of 2,6- bis- in methylene chloride (20mL) In solution be added 1- oxa- -6- azaspiro [3.4] octane (340mg, 3.01mmol), then be added triethylamine (303mg, 3.01mmol).The solution is stirred at room temperature 12 hours.By the reaction be allocated in methylene chloride (40mL) and water (30mL) it Between.Separate each layer.Organic layer is washed with salt water (30mL), is dried and concentrated, the chloro- 4- ethyl -6- of 2- (1- oxa- -6- is obtained Azaspiro [3.4] octyl- 6- yl) pyridine -3,5- dimethoxy nitrile (910mg, crude) is brown oil.LCMS m/z=303.0 [M+ H]+。
Step 6:4- ethyl -2- sulfydryl -6- (1- oxa- -6- azaspiro [3.4] octyl- 6- yl) pyridine -3,5- dimethoxy nitrile
The chloro- 4- ethyl -6- of 2- (1- oxa- -6- azaspiro [3.4] octyl- 6- yl) pyridine -3,5- dimethoxy nitrile (is being implemented Describe synthesis, 910mg, 3.01mmol in 3 step 2 of example) and thioacetic acid potassium (514mg, 4.51mmol) in N, N- dimethyl Mixture in formamide (10mL) is stirred at room temperature 1.5 hours and is directly used in next step.LCMS m/z=300.8 [M+H ]+。
Step 7:2- ((3,5- dicyano -4- ethyl -6- (1- oxa- -6- azaspiro [3.4] octyl- 6- yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides
Potassium carbonate (826mg, 6.00mmol) is added into said mixture and the reaction is stirred at room temperature 1 hour, so Be added afterwards methanesulfonic acid 2- amino -2- oxo -1- phenyl chlorocarbonate (describe synthesis in 3 step 5 of embodiment, 825mg, 3.60mmol).Gained mixture is stirred for 12 hours in room temperature, is then concentrated.The residue is pure by silica gel column chromatography Change (CH2Cl2: methanol 30:1), obtain 2- ((3,5- dicyano -4- ethyl -6- (1- oxa- -6- azaspiro [3.4] octyl- 6- yl) Pyridine -2- base) sulfenyl) -2- phenyl-acetamides (107mg, 8%) are pale solid.LCMS m/z=433.8 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 1.21 (t, J=7.6Hz, 3H), 2.17-2.06 (m, 1H), 2.41-2.33 (m, 1H), 2.85-2.63 (m, 4H), 4.05-3.71 (m, 3H), 4.13 (dd, J=28.3,12.7Hz, 1H), 4.52-4.40 (m, 2H), 5.61 (d, J=4.9Hz, 1H), 7.45-7.31 (m, 4H), 7.54 (d, J=7.5Hz, 2H), 7.93 (d, J=6.6Hz, 1H).
Embodiment 37:
2- ((6- (4- (3- aminopropyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides
Step 1:(3- (4- benzyl diethylenediamine -1- base) propyl) t-butyl carbamate
To 1- benzyl diethylenediamine (500mg, 2.84mmol) in CH3(3- bromopropyl) ammonia is added in solution in-CN (30mL) Base t-butyl formate (1.0g, 4.26mmol) and K2CO3(784mg, 5.68mmol).By the reaction after 70 DEG C are stirred 12 hours, The mixture is concentrated and surplus materials is passed through into silica gel chromatography (CH2Cl2: methanol 10:1), obtain (3- (4- benzyl piperazine Piperazine -1- base) propyl) t-butyl carbamate (900mg, 95%).LCMS m/z=334 [M+H]
Step 2:(3- (piperazine -1- base) propyl) t-butyl carbamate
By (3- (4- benzyl diethylenediamine -1- base) propyl) t-butyl carbamate (900mg, 2.7mmol) and palladium/carbon The mixture of (90mg) in methanol (30mL) is stirred overnight under room temperature nitrogen atmosphere.The reaction mixture is filtered, by the filter Remaining residue is simultaneously passed through silica gel chromatography (CH by liquid concentration2Cl2: methanol 5:1), obtain (3- (piperazine -1- base) third Base) t-butyl carbamate (460mg, 70% yield).LCMS m/z=244 [M+H]+。
Step 3:(3- (4- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) piperazine -1- base) propyl) carbamic acid The tert-butyl ester
To chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in 3 step 2 of embodiment, 426mg, (3- (piperazine -1- base) propyl) carbamic acid uncle 1.89mmol) is added in the solution in N,N-dimethylformamide (10mL) Butyl ester (460mg, 1.89mmol) and triethylamine (0.26mL, 1.89mmol).The reaction mixture is stirred at room temperature 5 minutes, Then it is allocated between ethyl acetate and water.Separate each layer.By organic layer water, salt water washing, it is dried and concentrated.It will be remaining Residue obtains (3- (4- (chloro- 3, the 5- dicyano -4- of 6- by silica gel chromatography (petroleum ether: ethyl acetate 40:60) Ethylpyridine -2- base) piperazine -1- base) propyl) t-butyl carbamate (600mg, 74%).LCMS m/z=433 [M+H]+。
Step 4:(3- (4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperazine -1- base) propyl) t-butyl carbamate
To (3- (4- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) piperazine -1- base) propyl) the tertiary fourth of carbamic acid Ester (300mg, 0.69mmol) be added in the solution in n,N-Dimethylformamide (7mL) thioacetic acid potassium (95mg, 0.83mmol).The reaction is stirred at room temperature 30 minutes, then by methanesulfonic acid 2- amino -2- oxo -1- phenylethylester ( Describe synthesis, 191mg, 0.83mmol in 3 step 5 of embodiment) and triethylamine (0.19mL, 1.38mmol) add to the reaction. The mixture is stirred at room temperature overnight.After water is added to the reaction, the solid by filtration of precipitation is collected and passes through silica gel Column chromatography purifies (CH2Cl2: methanol 20:1), obtain (3- (4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- Dicyano -4- ethylpyridine -2- base) piperazine -1- base) propyl) t-butyl carbamate (280mg, 72%), it is solid for yellow Body.LCMS m/z=564 [M+H]+。
Step 5:2- ((6- (4- (3- aminopropyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides
By (3- (4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) piperazine -1- base) propyl) t-butyl carbamate (280mg, 0.50mmol) and trifluoroacetic acid (3mL) be in methylene chloride Solution in (5mL) is stirred at room temperature overnight.The solvent is removed, by surplus materials saturation NaHCO3Aqueous solution, which neutralizes, to be used in combination Methylene chloride extraction.Organic layer is washed and is concentrated with saturated sodium-chloride water solution.The crude material is passed through into silica gel column chromatography Purify (CH2Cl2: methanol 5:1), obtain 2- ((6- (4- (3- aminopropyl) piperazine -1- base) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) sulfenyl) -2- phenyl-acetamides (91mg, 39%) are white solid.LCMS m/z=464 [M+H]+。1H NMR (400MHz, CD3OD) δ ppm 7.55 (d, J=6.7Hz, 2H), 7.45-7.36 (m, 3H), 5.49 (s, 1H), 4.05-3.94 (m, 4H), 3.09 (t, J=7.1Hz, 2H), 2.92 (q, J=7.6Hz, 2H), 2.68-2.53 (m, 6H), 1.94-1.85 (m, 2H), 1.32 (t, J=7.6Hz, 3H).4H is not observed.
Embodiment 38:
2- ((3,5- dicyano -4- ethyl -6- (1,7- diaza spiro [3.5] nonyl- 1- yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides trifluoroacetate
Step 1:4- methylenepiperidines base -1- t-butyl formate
Hydrogenation is added in tri- phenyl-bromide Phosphonium (9.5g, 26.7mmol) of Xiang Jiaji in the solution in tetrahydrofuran (30mL) Then dimethyl sulfoxide (33mL) is added in sodium (60%, 1.07g, 26.7mmol).Gained mixture is stirred 10 in environment temperature Minute, then with 4- oxo-piperidine base -1- t-butyl formate (5g, 25mmol) at the solution dropwise addition in tetrahydrofuran (20mL) Reason.Gained mixture is stirred 30 minutes in environment temperature, is then diluted with ethyl acetate (60mL).By the mixture water The washing of (60mL) and salt water (60mL) with sodium sulphate drying and is concentrated under reduced pressure.By residue chromatogram purification (petroleum ether: second Acetoacetic ester=30:1), title compound (4g, 80%) is obtained, is yellow oil.1H NMR (400MHz, chloroform-d) δ ppm 1.48 (s, 9H), 2.23-2.14 (m, 4H), 3.47-3.38 (m, 4H), 4.75 (s, 2H).
Step 2:1,7- diaza spiro [3.5] nonyl- 7- t-butyl formate
It is molten in methylene chloride (50mL) to 4- methylenepiperidines base -1- t-butyl formate (4g, 20mmol) at 0 DEG C Chlorosulphonyl isocyanate (3.4g, 24mmol) is added in liquid.Gained mixture is stirred overnight in environment temperature, then uses ether (100mL) dilutes and is cooled to 0 DEG C.At 0 DEG C, by the mixture sodium thiosulfate (9.5g, 60mmol) and potassium hydroxide The solution processing of (2.24g, 40mmol) in water (50mL).Gained mixture is stirred 3 hours at 0 DEG C and uses ethyl acetate (2x 50mL) extraction.It by the drying of organic phase anhydrous sodium sulfate and is concentrated under reduced pressure, obtains yellow oil (4.1g is crude).By the oil It is dissolved in tetrahydrofuran (30mL) and borane-dimethyl sulfide complex compound (2M, 15mL, 30mmol) is added.By gained mixture It is stirred overnight at 70 DEG C.The mixture is cooled to environment temperature and is concentrated under reduced pressure to give title compound (4.5g, crude), For yellow oil, it is used in next step without being further purified.LCMS m/z=227.1 [M+H]+。
Step 3:1- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) -1,7- diaza spiro [3.5] nonyl- 7- formic acid The tert-butyl ester
At 0 DEG C, by 1,7- diaza spiro [3.5] nonyl- 7- t-butyl formate (1.5g, crude) and 2, the chloro- 4- ethyl of 6- bis- Pyridine -3,5- dimethoxy nitrile (describing synthesis, 1g, 4.5mmol in 3 step 2 of embodiment) is dissolved in tetrahydrofuran (20mL) simultaneously It is added triethylamine (1.14g, 11.25mmol).Gained mixture is stirred 2 hours in environment temperature, then uses ethyl acetate (60mL) dilution.The mixture is washed with water (40mL) and salt water (40mL), with anhydrous sodium sulfate drying and is concentrated under reduced pressure, obtains It is yellow oil to title compound (2.1g, crude), is used in next step without being further purified.LCMS m/z= 437.8[M+Na]+。
Step 4:1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) -1,7- diaza spiro [3.5] nonyl- 7- t-butyl formate
To the tertiary fourth of 1- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) -1,7- diaza spiro [3.5] nonyl- 7- formic acid Ester (2.1g, crude) be added in the solution in anhydrous n,N-Dimethylformamide (30mL) thioacetic acid potassium (0.7g, 6mmol).Gained mixture is stirred at room temperature and potassium carbonate (1.65g, 12mmol) is then added within 3 hours and by the reaction in room Temperature stirring 2 hours.Then methanesulfonic acid 2- amino -2- oxo -1- phenylethylester is added and (describes conjunction in 3 step 5 of embodiment It is stirred at room temperature overnight at 2.75g, 12mmol) and by gained mixture, is then diluted with ethyl acetate (80mL), use water The washing of (60mL) and salt water (60mL).By organic phase anhydrous sodium sulfate drying and it is concentrated under reduced pressure.By residue column color Spectrum purifying (petroleum ether: ethyl acetate=1:1-1:2), obtains title compound (1g, crude).LCMS m/z=546.8 [M+H ]+。
Step 5:2- ((3,5- dicyano -4- ethyl -6- (1,7- diaza spiro [3.5] nonyl- 1- yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides trifluoroacetate
At 0 DEG C, to 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) -1,7- diaza spiro [3.5] nonyl- 7- t-butyl formate (0.9g, crude) is in the solution in Isosorbide-5-Nitrae-dioxanes (20mL) It is bubbled HCl (g) 10 minutes.Gained mixture is concentrated under reduced pressure, then residue preparative-HPLC is purified, is obtained It is white solid to title compound (120mg, 15%).LCMS m/z=447.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 1.2 (t, J=6Hz, 3H), 2.36-2.18 (m, 4H), 2.70 (q, J=6Hz, 2H), 3.18-3.12 (m, 2H), 3.54-3.46 (m, 4H), 3.65-3.57 (m, 2H), 5.55-5.44 (m, 2H), 7.53-7.35 (m, 4H), 7.95-7.88 (m, 1H), 8.71-8.59 (br, 2H).
Embodiment 39:
2- ((3,5- dicyano -4- cyclopropyl -6- (4- (pyrrolidin-1-yl methyl) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides
Step 1:4- (pyrrolidin-1-yl methyl) piperidyl -1- t-butyl formate
Exist to 4- formyl piperidine base -1- t-butyl formate (1g, 4.69mmol) and pyrrolidines (0.3g, 4.22mmol) 2 drop acetic acid are added in solution in methylene chloride (20mL).The mixture is stirred 1 hour, triacetoxy borohydride is then added Sodium hydride (1g, 4.7mmol).The mixture is stirred 1 hour, sodium hydrate aqueous solution (2M, 2x 50mL) and HCl are then used Aqueous solution (2M, 2x 50mL) washing, is dried, filtered and concentrated with anhydrous sodium sulfate, and obtaining title compound, (1g, 80% produces Rate).LCMS m/z=269 [M+H]+。
Step 2:4- (pyrrolidin-1-yl methyl) piperidine hydrochlorate
4- (pyrrolidin-1-yl methyl) piperidines is added in the solution in dioxanes (4M, 20mL, 80mmol) to hydrochloric acid Base -1- t-butyl formate (1g, 3.73mmol).The mixture is stirred 2 hours and obtained solid is collected by filtration, uses second Acetoacetic ester washs and is dried to obtain crude title compound (0.8g, > 100% thick yield).LCMS m/z=169 [M+H]+。
The chloro- 4- cyclopropyl -6- of step 3:2- (4- (pyrrolidin-1-yl methyl) piperidin-1-yl) pyridine -3,5- dimethoxy nitrile
To chloro- 4- cyclopropyl pyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in 4 step 2 of embodiment, 500mg, 2.1mmol) and 4- (pyrrolidin-1-yl methyl) piperidine hydrochlorate (500mg, 2.4mmol) is molten in methylene chloride (20mL) Triethylamine (750mg, 7.5mmol) is added in liquid.The mixture is stirred 1 hour, is then washed with salt water (2x 100mL), is used Anhydrous sodium sulfate is dried and concentrated.Then by the residue silica gel chromatography, with ethyl acetate: petroleum ether (1:3) is eluted, Obtain title compound (750mg, 96% yield).LCMS m/z=370 [M+H]+。
Step 4:4- cyclopropyl -2- sulfydryl -6- (4- (pyrrolidin-1-yl methyl) piperidin-1-yl) pyridine -3,5- diformazan Nitrile
To the chloro- 4- cyclopropyl -6- of 2- (4- (pyrrolidin-1-yl methyl) piperidin-1-yl) pyridine -3,5- dimethoxy nitrile (750mg, 2.0mmol) in the solution in n,N-Dimethylformamide (20mL) be added thioacetic acid potassium (250mg, 2.2mmol).The mixture is stirred 2 hours, is then diluted with ethyl acetate (200mL), is washed with salt water (2x 100mL), It is dried and concentrated with anhydrous sodium sulfate, obtains crude title compound (700mg, 95% thick yield).LCMS m/z=368 [M +H]+。
Step 5:2- ((3,5- dicyano -4- cyclopropyl -6- (4- (pyrrolidin-1-yl methyl) piperidin-1-yl) pyridine - 2- yl) sulfenyl) -2- phenyl-acetamides
To 4- cyclopropyl -2- sulfydryl -6- (4- (pyrrolidin-1-yl methyl) piperidin-1-yl) pyridine -3,5- dimethoxy nitrile Methanesulfonic acid 2- amino -2- oxo -1- benzene is added in (700mg, 1.9mmol) in the solution in n,N-Dimethylformamide (50mL) Base ethyl ester (describing synthesis, 500mg, 2.2mmol in 3 step 5 of embodiment) and potassium carbonate (300mg, 2.2mmol).It will The reaction mixture is stirred overnight in environment temperature.The mixture is diluted with ethyl acetate (200mL) and with salt water (2x It 100mL) washs, is dried and concentrated with anhydrous sodium sulfate.Residue preparative-HPLC is purified, title compound is obtained (15mg, 1.5% yield).LCMS m/z=501 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.92 (s, 1H), 7.52 (d, J=7.0Hz, 2H), 7.41-7.34 (m, 3H), 5.53 (s, 1H), 4.53 (t, J=12.2Hz, 2H), 3.60 (br S, 3H), 3.17-3.10 (m, 3H), 3.04 (br s, 2H), 2.18-1.99 (m, 4H), 1.93-1.86 (m, 3H), 1.34-1.22 (m, 3H), 1.18-1.09 (m, 2H), 0.98 (dt, J=10.2,5.2Hz, 2H).
Embodiment 40:
2- ((3,5- dicyano -4- cyclopropyl -6- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides
To chloro- 4- cyclopropyl pyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in 4 step 2 of embodiment, 300mg, 1.26mmol) and 1- methyl -4- (piperidin-4-yl) piperazine hydrochloride (243mg, 1.10mmol) is in methylene chloride (50mL) Triethylamine (300mg, 2.75mmol) is added in solution.The mixture is stirred 1 hour, is then concentrated.To the residue in N, Thioacetic acid potassium (144mg, 1.26mmol) is added in solution in dinethylformamide (50mL) and stirs the mixture Overnight.Potassium carbonate (500mg, 3.62mmol) and methanesulfonic acid 2- amino -2- oxo -1- phenylethylester are added into the mixture (describing synthesis, 1g, 4.46mmol in 3 step 5 of embodiment).The reaction is stirred overnight in environment temperature, then uses water (30mL) dilution.Obtained solid is collected by filtration, then with preparative-HPLC purify, obtain title compound (200mg, 37% yield).LCMS m/z=516 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.94 (s, 1H), 7.53 (d, J= 7.1Hz, 2H), 7.43-7.30 (m, 4H), 5.54 (s, 1H), 4.61 (s, 4H), 3.36-2.98 (m, 8H), 2.83 (s, 3H), 2.08-1.95 (m, 4H), 1.54 (dd, J=24.5,11.2Hz, 2H), 1.14 (dt, J=8.6,3.1Hz, 2H), 1.04-0.92 (m, 2H).
Embodiment 41:
(R) -2- ((3,5- dicyano -6- (1,4- Diazesuberane -1- base) -4- ethylpyridine -2- base) amino) - 2- phenyl-acetamides
Step 1:(R) -2- ((the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) amino) -2- phenyl-acetamides
At 20 DEG C, chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- of tetrahydrofuran (10mL) will be dissolved in (in embodiment Synthesis, 148.5mg, 0.657mmol are described in 3 steps 2) agitating solution (R) -2- amino -2- phenyl-acetamides (118mg, 0.788mmol) is disposably handled.After 2 hours, which is diluted with EtOAc (50mL), with water (3x 50mL), salt water washing, it is dry, it is then concentrated, obtains (R) -2- ((chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-) ammonia Base) -2- phenyl-acetamides (177mg, 0.521mmol, 79% yield) are light yellow solid.LCMS m/z=340 [M+H ]+。
Step 2:(R) -2- ((3,5- dicyano -6- (1,4- Diazesuberane -1- base) -4- ethylpyridine -2- base) Amino) -2- phenyl-acetamides
In room temperature, by (R) -2- ((6- chloro- 3,5- dicyano -4- ethylpyridine -2- base) amino) -2- phenyl-acetamides The solution of (39mg, 0.115mmol) in tetrahydrofuran (5mL) is existed with Isosorbide-5-Nitrae-Diazesuberane (184mg, 1.836mmol) Solution in tetrahydrofuran (5mL) is disposably handled.Gained suspension is stirred at room temperature 1 hour, then mixes the reaction Object is diluted with ethyl acetate (20mL), and with water (2x 20mL), salt water washing is then dry with sodium sulphate, obtains raw product. The material is purified on 24g Analogix column, which is pre-processed with methylene chloride, is then washed with 100%DCM (4 minutes) It is de-, then with (methanol contains 10% ammonium hydroxide)/dichloromethane eluent 25 minutes of 0-100% gradient.By required grade division And be concentrated in vacuo, it is then dried in vacuo, obtains (R) -2- ((3,5- dicyano -6- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -4- Ethylpyridine -2- base) amino) -2- phenyl-acetamides (23mg, 0.057mmol, 50% yield) are white solid.LCMS M/z=404 [M+H]+。1H NMR (400MHz, DMSO-d6): δ ppm 7.83 (s, 1H), 7.49-7.42 (m, 3H), 7.38- 7.31 (m, 2H), 7.31-7.25 (m, 1H), 7.07 (d, J=6.1Hz, 1H), 5.42 (d, J=6.1Hz, 1H), 3.86-3.61 (m, 5H), 2.90-2.79 (m, 1H), 2.71 (q, J=7.7Hz, 3H), 2.61 (t, J=5.7Hz, 2H), 1.72 (dd, J= 13.3,7.5Hz, 1H), 1.65-1.55 (m, 1H), 1.20 (t, J=7.6Hz, 3H).
Embodiment 42:
2- ((3,5- dicyano -4- cyclopropyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides trifluoroacetate
To chloro- 4- cyclopropyl pyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in 4 step 2 of embodiment, 500mg, 2.10mmol) add in the solution in methylene chloride (50mL) with 4- (pyrrolidin-1-yl) piperidyl (325mg, 2.11mmol) Enter triethylamine (230mg, 2.28mmol).The reaction is stirred at room temperature until LCMS shows the product.The mixture is concentrated Obtain light yellow solid, be dissolved in n,N-Dimethylformamide (50mL) and be added thioacetic acid potassium (144mg, 1.26mmol).The mixture is stirred 6 hours at 25 DEG C, potassium carbonate (500mg, 3.60mmol) and methanesulfonic acid 2- is then added Amino -2- oxo -1- phenylethylester (describing synthesis, 1.0g, 4.36mmol in 3 step 5 of embodiment).By the mixture It is stirred at room temperature overnight.The mixture is diluted with water (30mL) and is extracted with ethyl acetate (30mL).The organic phase is concentrated, Then residue preparative-HPLC is purified, obtains title compound (120mg, 22% yield).LCMS m/z=487 [M+H]+。1H NMR (400MHz, CDCl3) δ ppm 12.25 (s, 1H), 7.54-7.45 (m, 2H), 7.44-7.34 (m, 3H), 6.95 (s, 1H), 6.88 (s, 1H), 5.30 (s, 1H), 4.72 (t, J=12.3Hz, 2H), 3.92 (d, J=38.7Hz, 2H), 3.32 (t, J=13.1Hz, 1H), 3.12 (s, 1H), 3.06-2.94 (m, 1H), 2.84 (s, 4H), 2.24-2.12 (m, 6H), 1.92 (d, J=8.3Hz, 1H), 1.36-1.14 (m, 4H).
Embodiment 43:
2- ((3,5- dicyano -4- ethyl -6- (2,7- diaza spiro [3.5] nonyl- 7- yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides
Step 1:7- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) -2,7- diaza spiro [3.5] nonyl- 2- formic acid The tert-butyl ester
To chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in 3 step 2 of embodiment, 452mg, 2mmol) be added in the solution in methylene chloride (20mL) 2,7- diaza spiro [3.5] nonyl- 2- t-butyl formate (452mg, 2mmol), triethylamine (202mg, 2mmol) then is added.The reaction is stirred 12 hours and is diluted simultaneously with methylene chloride (40mL) It is washed with water (25mL) and salt water (25mL).Organic layer is dried and concentrated with sodium sulphate, obtains crude title compound (820mg) is yellow solid.LCMS m/z=438 [M+Na]+。
Step 2:7- (3,5- dicyano -4- ethyl -6- mercaptopyridine -2- base) -2,7- diaza spiro [3.5] nonyl- 2- first Tert-butyl acrylate
To crude 7- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) -2,7- diaza spiro [3.5] nonyl- 2- first Thioacetic acid potassium is added in the solution in n,N-Dimethylformamide (8mL) in tert-butyl acrylate (820mg, it is assumed that 1.97mmol) (271mg, 2.36mmol).Gained mixture is stirred 2 hours in environment temperature.Then the mixture is diluted with water (25mL) And it is extracted with ethyl acetate (40mL).Organic phase is washed with salt water (25mL), it is dry, and be concentrated, it obtains crude titled It closes object (890mg), is brown oil.LCMS m/z=414 [M+H]+。
Step 3:7- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) -2,7- diaza spiro [3.5] nonyl- 2- t-butyl formate
To crude 7- (3,5- dicyano -4- ethyl -6- mercaptopyridine -2- base) -2,7- diaza spiro [3.5] nonyl- 2- Potassium carbonate (594mg, 4.3mmol) is added in t-butyl formate (890mg) in the solution in n,N-Dimethylformamide (6mL). The mixture is stirred 1 hour in environment temperature, methanesulfonic acid 2- amino -2- oxo -1- phenylethylester is then added and (is implementing Synthesis, 741mg, 3.23mmol are described in 3 step 5 of example).Gained mixture is stirred 12 hours in environment temperature.Then will The mixture is diluted with ethyl acetate (60mL), is washed, is dried and concentrated with water (30mL) and salt water (30mL).By the residue With silica gel chromatography, is eluted with petroleum ether-ethyl acetate (2:1), obtain title compound (600mg, 55% yield, through 3 Step), it is brown solid.LCMS m/z=547 [M+H]+。
Step 4:2- ((3,5- dicyano -4- ethyl -6- (2,7- diaza spiro [3.5] nonyl- 7- yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides
To 7- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) - 2,7- diaza spiros [3.5] nonyl- 2- t-butyl formate (600mg, 1.1mmol) is added in the solution in methylene chloride (20mL) Trifluoroacetic acid (2mL).Acquired solution is stirred 5 hours and is concentrated under reduced pressure in environment temperature.By the residue ethyl acetate (60mL) is diluted and is washed with sodium bicarbonate aqueous solution (40mL), and drying is simultaneously concentrated under reduced pressure.The residue silica gel chromatograph is pure Change, is eluted with methylene chloride-methanol (10:1), obtain solid, it is washed and dried with ether, title compound is obtained (90.8mg, 18% yield), is light yellow solid.LCMS m/z=447 [M+H]+。1H NMR (400MHz, DMSO-d6)δ Ppm 9.09 (br s, 2H), 7.99 (s, 1H), 7.53 (d, J=7.1Hz, 2H), 7.45-7.26 (m, 4H), 5.55 (s, 1H), 3.81 (t, J=5.3Hz, 4H), 3.77 (s, 4H), 2.76 (q, J=7.5Hz, 2H), 1.97-1.82 (m, 4H), 1.21 (t, J= 7.6Hz, 3H).
Embodiment 44:
2- ((3,5- dicyano -4- ethyl -6- (2,6- diaza spiro [3.4] octyl- 6- yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides
Step 1:6- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) -2,6- diaza spiro [3.4] octane -2- first Tert-butyl acrylate
To chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in 3 step 2 of embodiment, 900mg, 4mmol) and 2,6- diaza spiro [3.4] octane -2- t-butyl formate (840mg, 4mmol) is in methylene chloride (100mL) Triethylamine (400mg, 4mmol) is added in solution.The reaction is stirred 30 minutes, is then washed and is incited somebody to action with salt water (2x 100mL) Organic phase is dried and concentrated with sodium sulphate.By the residue silica gel chromatography, eluted with petroleum ether-ethyl acetate (3:1), Obtain title compound (1.3g, 81% yield).LCMS m/z=346 [M+H-isobutene]+。
Step 2:6- (3,5- dicyano-4- ethyl-6- mercaptopyridine-2- base)-2,6- diaza spiro [3.4] octane-2- T-butyl formate
To 6- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) -2,6- diaza spiro [3.4] octane -2- formic acid uncle Butyl ester (1.3g, 3.2mmol) be added in the solution in n,N-Dimethylformamide (20mL) thioacetic acid potassium (554mg, 4.8mmol).The reaction is stirred 3 hours and is then diluted the mixture with ethyl acetate (200mL) and with salt water (2x 100mL) wash.The organic phase is concentrated, crude title compound (1g, 78% thick yield) is obtained.LCMS m/z=344 [M + H-isobutene]+。
Step 3:6- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) -2,6- diaza spiro [3.4] octane -2- t-butyl formate
To crude 6- (3,5- dicyano -4- ethyl -6- mercaptopyridine -2- base) -2,6- diaza spiro [3.4] octane - Methanesulfonic acid 2- ammonia is added in 2- t-butyl formate (1g, it is assumed that 2.5mmol) in the solution in n,N-Dimethylformamide (100mL) Base -2- oxo -1- phenylethylester (describing synthesis, 0.572g, 2.5mmol in 3 step 5 of embodiment) and potassium carbonate (1.0g, 7.2mmol).The reaction is stirred overnight and is then diluted with ethyl acetate (200mL) and is washed with salt water (2x 100mL) It washs.Organic phase is dried, filtered and concentrated with sodium sulphate, obtains crude title compound (0.8g, 60% thick yield).LCMS M/z=477 [M+H-isobutene]+。
Step 4:2- ((3,5- dicyano -4- ethyl -6- (2,6- diaza spiro [3.4] octyl- 6- yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides
To crude 6- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) -2,6- diaza spiro [3.4] octane -2- t-butyl formate (0.8g, it is assumed that 1.5mmol) is in methylene chloride (10mL) Solution in be added trifluoroacetic acid (2mL).The reaction is stirred overnight and is then concentrated.The residue is pure with preparative-HPLC Change, obtains title compound (520mg, 80% yield).LCMS m/z=433 [M+H]+。1H NMR (400MHz, DMSO-d6)δ Ppm8.48 (s, 1H), 8.08 (s, 1H), 7.54 (d, J=7.3Hz, 2H), 7.42-7.31 (m, 4H), 5.63 (s, 1H), 4.22- 3.77 (m, 8H), 2.75 (q, J=7.4Hz, 2H), 2.26 (s, 2H), 1.29-1.10 (m, 3H).
Embodiment 46:
2- ((3,5- dicyano -4- cyclopropyl -6- (1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) propionyl Amine
Step 1:4- (6- ((1- amino -1- oxo propyl- 2- yl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine -2- Base) -1,4- Diazesuberane -1- t-butyl formate
By the tertiary fourth of 4- (the chloro- 3,5- dicyano -4- cyclopropyl pyridine -2- base of 6-) -1,4- Diazesuberane -1- formic acid Ester (describing synthesis, 300mg, 0.74mmol in 4 step 3 of embodiment), KSAc (93mg, 0.81mmol) are in N, N- dimethyl Mixture in formamide (8mL) is stirred at room temperature 30 minutes, and 2- bromine propionamide (136mg, 0.89mmol) then is added.By institute Mixture is obtained to be stirred at room temperature 12 hours.By the reaction mixture down in water (50mL), then ethyl acetate (2x 50mL) is used Extraction.Combined organic layer is dry, and concentration by the residue silica gel chromatography, uses CH2Cl2: MeOH (100:1), Title compound (290mg, 83% yield) is obtained, is white solid.LCMS m/z=371.0 [M+H-Boc]+。
Step 2:2- ((3,5- dicyano -4- cyclopropyl -6- (1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) propionamide
By 4- (6- ((1- amino -1- oxo propyl- 2- yl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine -2- base) -1, 4- Diazesuberane -1- t-butyl formate (describing synthesis, 260mg, 0.55mmol in 6 step 1 of embodiment) and trifluoro Acetic acid (1mL) is in CH2Cl2Mixture in (6mL) is stirred at room temperature 12 hours.Gained mixture is concentrated.The residue is fallen Into water (50mL) and by the way that NaHCO is added3Aqueous solution alkalizes, and then uses CH2Cl2(2x 50mL) extraction.By merging Organic layer is dried and concentrated.By the residue silica gel chromatography, CH is used2Cl2: MeOH (30:1) elution obtains title compound Object (80mg, 39% yield), is white solid.LCMS m/z=371 [M+H]+。1H NMR (400MHz, CDCl3)δppm 6.44 (br s, 1H), 5.35 (br s, 1H), 4.22 (q, J=7.6Hz, 1H), 4.06-3.97 (m, 1H), 3.97-3.87 (m, 3H), 3.16-3.10 (m, 2H), 2.97-2.85 (m, 2H), 2.10-2.02 (m, 1H), 2.01-1.94 (m, 2H), 1.86 (br S, 2H), 1.64 (d, J=7.6Hz, 3H), 1.35-1.23 (m, 2H), 1.15-1.05 (m, 2H).
Embodiment 47:
2- ((3,5- dicyano -4- ethyl -6- (4- (2- oxo-imidazole alkane -1- base) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides
By 2- ((the bromo- 3,5- dicyano -4- ethylpyridine -2- base of 6-) sulfenyl) -2- phenyl-acetamides (in 6 step of embodiment Synthesis, 15mg, 0.04mmol are described in rapid 1) solution 1- (piperidin-4-yl) imidazoline -2- in tetrahydrofuran (1mL) Keto hydrochloride (12mg, 0.06mmol) and triethylamine (0.013mL, 0.09mmol) processing are simultaneously stirred 72 hours in environment temperature. By the product mixtures dry method loading to SiO2(0.9g) and in SiO2(4g RediSep column, uses 0-15% to upper progress chromatogram purification MeOH/CH2Cl2Elution), title compound (15mg, 82% yield) is obtained, is pale solid.LCMS m/z=490 [M+ H]+。1H NMR (300MHz, DMSO-d6) δ ppm 7.93 (br s, 1H), 7.52 (br d, J=6.8Hz, 2H), 7.46-7.30 (m, 4H), 6.32 (s, 1H), 5.54 (s, 1H), 4.67 (br d, J=12.9Hz, 2H), 3.93-3.64 (m, 2H), 3.30- 3.06 (m, 7H), 2.76 (q, J=7.0Hz, 2H), 1.82-1.50 (m, 2H), 1.19 (t, J=7.5Hz, 3H).
Embodiment 48:
2- ((3,5- dicyano -4- ethyl -6- (4- hydroxy piperidine -1- base) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine
By 2- ((the bromo- 3,5- dicyano -4- ethylpyridine -2- base of 6-) sulfenyl) -2- phenyl-acetamides (in 6 step of embodiment Synthesis, 16mg, 0.04mmol are described in rapid 1) solution in tetrahydrofuran (1mL) with 4- hydroxy piperidine base (14mg, It 0.14mmol) handles and is stirred 3 hours in environment temperature.Then by the reaction loading to SiO2(0.9g) and in SiO2Upper progress (4g RediSep column, uses 0-15%MeOH/CH to chromatogram purification2Cl2Elution), title compound (15mg, 88% yield) is obtained, It is white solid.LCMS m/z=420 [M-H]–。1H NMR (300MHz, DMSO-d6) δ ppm 7.92 (s, 1H), 7.57- 7.46 (m, 2H), 7.44-7.28 (m, 4H), 5.53 (s, 1H), 4.85 (d, J=4.1Hz, 1H), 4.24-4.05 (m, 2H), 3.91-3.70 (m, 1H), 3.65-3.47 (m, 2H), 2.75 (q, J=7.4Hz, 2H), 1.84 (br s, 2H), 1.61-1.34 (m, 2H), 1.20 (t, J=7.6Hz, 3H).
Embodiment 49:
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide
By 2- ((the bromo- 3,5- dicyano -4- ethylpyridine -2- base of 6-) sulfenyl) -2- phenyl-acetamides (in 6 step of embodiment Synthesis, 17mg, 0.04mmol are described in rapid 1) solution (S) -3- pyrrolidinol in tetrahydrofuran (1mL) (0.009mL, 0.11mmol) processing is stirred 3 hours in environment temperature.Then by the reaction loading to SiO2(0.9g) and SiO2(4g RediSep column, uses 0-15%MeOH/CH to upper progress chromatogram purification2Cl2Elution), obtain title compound (12mg, 70% yield), it is white solid.LCMS m/z=408 [M+H]+。1H NMR (300MHz, DMSO-d6)δppm 7.91(br S, 1H), 7.52 (br d, J=7.2Hz, 2H), 7.44-7.26 (m, 4H), 5.61 (s, 1H), 5.15 (br s, 1H), 4.42 (br S, 1H), 3.90 (br s, 2H), 3.85-3.64 (m, 2H), 2.89-2.56 (m, 2H), 1.95 (br s, 2H), 1.20 (br t, J =7.3Hz, 3H).
Embodiment 50:
2- ((3,5- dicyano -4- ethyl -6- (3- oxypiperazin -1- base) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine
The chloro- 4- ethyl -6- of step 1:2- (3- oxypiperazin -1- base) pyridine -3,5- dimethoxy nitrile
To chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in 3 step 2 of embodiment, 2.26g, Piperazine -2- ketone (1.001g, 10.00mmol) and triethylamine 10.00mmol) are added in the solution in methylene chloride (30mL) (1.012g, 10.00mmol).The mixture is stirred 12 hours at 25 DEG C.By the reaction mixture with methylene chloride (30mL) Dilution, is washed with water (30mL) and salt water (30mL), is dried and concentrated to obtain title compound (2.4g, 83% yield), is Light yellow solid.LCMS m/z=290 [M+H]+。
Step 2:4- ethyl -2- sulfydryl -6- (3- oxypiperazin -1- base) pyridine -3,5- dimethoxy nitrile
Exist to the chloro- 4- ethyl -6- of 2- (3- oxypiperazin -1- base) pyridine -3,5- dimethoxy nitrile (290mg, 1.001mmol) Thioacetic acid potassium (229mg, 2.002mmol) is added in solution in n,N-Dimethylformamide (5mL).By the mixture in room Temperature stirring 12 hours, is diluted with ethyl acetate (60mL) and is washed with saturated aqueous ammonium chloride (60mL).By organic phase salt Water (60mL) washing, is dried and concentrated to obtain crude 4- ethyl -2- sulfydryl -6- (3- oxypiperazin -1- base) pyridine -3,5- bis- Formonitrile HCN (300mg), is brown solid.LCMS m/z=288 [M+H]+。
Step 3:2- ((3,5- dicyano -4- ethyl -6- (3- oxypiperazin -1- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide
To crude 4- ethyl -2- sulfydryl -6- (3- oxypiperazin -1- base) pyridine -3,5- dimethoxy nitrile (300mg, Potassium carbonate 1.044mmol) is added in the solution in N,N-dimethylformamide (6mL) (to describe in 3 step 5 of embodiment Synthesis, 289mg, 2.088mmol).The mixture is stirred at room temperature 2 hours, methanesulfonic acid 2- amino -2- oxo -1- is then added Phenylethylester (describes synthesis, 287mg, 1.253mmol in 3 step 5 of embodiment).The mixture is stirred at room temperature 12 Hour.The reaction solution is diluted with ethyl acetate (60mL), is washed with water (60mL) and salt water (60mL), dry, concentration is simultaneously It is purified with preparative-HPLC, obtains 2- ((3,5- dicyano -4- ethyl -6- (3- oxypiperazin -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides (35mg, 8% yield) are Light brown solid.LCMS m/z=421.0 [M+H]+。1H NMR (400MHz, DMSO-d6) 8.30 (s, 1H), 7.95 (s, 1H), 7.54 (d, J=7.1Hz, 2H), 7.46-7.24 (m, 4H), 5.57 (s, 1H), 4.39 (s, 2H), 4.07-3.97 (m, 2H), 2.78 (dd, J=8Hz, 7.5Hz, 2H), 1.22 (t, J= 7.5Hz, 3H).
Embodiment 51:
2- [(6- amino -3,5- dicyano -4- cyclopropyl -2- pyridyl group) sulfanyl] -2- phenvl-acetamide
Step 1:2- amino -4- cyclopropyl -6- mercaptopyridine -3,5- dimethoxy nitrile；4- methyl morpholine
By 2- cyano-thioacetamide (860mg, 8.56mmol), N-methylmorpholine (2.2mL, 20mmol) and cyclopropane Formaldehyde (0.32mL, 4.28mmol) is mixed and is dissolved in ethyl alcohol (10mL).Acquired solution is stirred 16 hours in environment temperature.By institute The precipitating ethanol washing of formation is simultaneously dried under reduced pressure, and obtains title compound (322mg, 24% yield), is that paste is coloured solid Body.LCMS m/z=217 [M+H]+。
Step 2:2- ((6- amino -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- phenyl-acetamides
By 2- amino -4- cyclopropyl -6- mercaptopyridine -3,5- dimethoxy nitrile；4- methyl morpholine, (316mg, 1mmol) and 2- Chloro- 2- phenvl-acetamide (174mg, 1.02mmol) is dissolved in n,N-Dimethylformamide (10mL) and the reaction mixture exists Environment temperature stirs 16 hours.The mixture is diluted with EtOAc (50mL) and with water (3x 10mL), saturated sodium-chloride (10mL), then water (10mL) washs.By the drying of organic layer anhydrous sodium sulfate and it is concentrated under reduced pressure.By raw product preparative HPLC purifying, obtains title compound (7mg, 2% yield), is white solid.LCMS m/z=348 [M-H]–.1H NMR (300MHz, DMSO-d6) δ ppm 7.80 (br s, 2H), 7.73 (s, 1H), 7.58 (dd, J=1.6,7.9Hz, 2H), 7.39- 7.26 (m, 4H), 5.54 (s, 1H), 2.15-2.00 (m, 1H), 1.25-0.95 (m, 4H).
Embodiment 52:
2- ((3,5- dicyano -4- ethyl -6- (methylamino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides
Step 1:2- ((the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) sulfenyl) -2- phenyl-acetamides
By 2- ((6- amino -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides (in embodiment 1 In describe synthesis, 74mg, 0.22mmol) suspension of stirring in anhydrous acetonitrile (10mL) with copper chloride (II) (52mg, It 0.39mmol) is handled with isoamyl nitrite (0.052mL, 0.39mmol), is then heated to 70 DEG C in a nitrogen atmosphere and continues 45 minutes.Then be added more copper chlorides (II) (52mg, 0.39mmol) and isoamyl nitrite (0.052mL, 0.39mmol).After forty minutes, carry out the continuous addition of third time: copper chloride (II) (52mg, 0.39mmol), then nitrous acid is different Pentyl ester (0.052mL, 0.39mmol).After 1 hour, which is evaporated in vacuo to doing, crude title compound is obtained Object is employed without and is further purified.LCMS m/z=355 [M-H]–.
Step 2:2- ((3,5- dicyano -4- ethyl -6- (methylamino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides
By crude 2- ((chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-) sulfenyl) -2- phenyl-acetamides, The solution of (39.25mg, 0.11mmol) in tetrahydrofuran (3mL) and ethyl alcohol (1.5mL) methylamine solution (tetrahydrofuran of 2M Solution, 0.44mL, 0.88mmol) processing, then heated at 65 DEG C.After 45 minutes, more methylamine solutions (tetrahydro of 2M is added Tetrahydrofuran solution, 0.11mL, 0.22mmol) and it is further continued for heating 45 minutes.Then the reaction mixture is cooling and by its loading To SiO2(1g)。SiO2(12g RediSep column, uses 0-10%MeOH/CH to upper chromatography2Cl2Elution), 14mg material is obtained, then It is dissolved in DMSO (0.4mL), uses 50%CH3-CN/H2O (0.4mL) dilutes and collects obtained solid and use 50%CH3-CN/ H2O (5mL) washing obtains title compound (7mg), is pale solid.LCMS m/z=350 [M-H]–。1H NMR (300MHz, DMSO-d6) δ ppm 8.08 (br d, J=4.3Hz, 1H), 7.91 (br s, 1H), 7.64-7.46 (m, 2H), 7.45-7.29 (m, 4H), 5.64 (s, 1H), 2.99 (br d, J=4.5Hz, 3H), 2.69 (d, J=7.4Hz, 2H), 1.17 (t, J=7.5Hz, 3H).
Embodiment 53:
2- ((3,5- dicyano -4- ethyl -6- ((2- methoxy ethyl) (methyl) amino) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides
By 2- ((the bromo- 3,5- dicyano -4- ethylpyridine -2- base of 6-) sulfenyl) -2- phenyl-acetamides (in 6 step of embodiment Synthesis, 20mg, 0.05mmol are described in rapid 1) solution (2- methoxy ethyl)-methylamine in tetrahydrofuran (1mL) (0.012mL, 0.11mmol) is handled 18 hours in environment temperature, loading to SiO2(4g) and in SiO2Upper progress chromatogram purification (4g RediSep column, uses 0-5%MeOH/CH2Cl2Elution), title compound (16mg, 78% yield) is obtained, is white solid. LCMS m/z=410 [M+H]+。1H NMR (300MHz, DMSO-d6) δ ppm 7.90 (s, 1H), 7.55-7.45 (m, 2H), 7.43-7.30 (m, 4H), 5.53 (s, 1H), 4.00 (s, 1H), 3.93 (s, 1H), 3.56 (t, J=5.2Hz, 2H), 3.37 (s, 3H), 3.26 (s, 3H), 2.76 (q, J=7.5Hz, 2H), 1.20 (t, J=7.6Hz, 3H).
Embodiment 54:
2- ((3,5- dicyano -4- ethyl -6- (3- methoxyl group azetidine -1- base) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides
By 2- [(the bromo- 3,5- dicyano -4- ethyl -2- pyridyl group of 6-) sulfanyl] -2- phenvl-acetamide (in embodiment Synthesis, 20mg, 0.05mmol are described in 6 steps 1) solution 3- methoxyl group azetidine in tetrahydrofuran (1mL) Hydrochloride (16mg, 0.13mmol) and triethylamine (0.02mL, 0.13mmol) processing.Acquired solution is stirred 45 in environment temperature Minute, dry method loading to SiO2(0.9g) and in SiO2Chromatogram purification is carried out on (4g RediSep column), uses 0-5%MeOH/ CH2Cl2Elution, obtains 2- [[3,5- dicyano -4- ethyl -6- (3- methoxyl group azetidine -1- base) -2- pyridyl group] sulfane Base] -2- phenvl-acetamide (20mg, 100% yield) is white solid.LCMS m/z=408 [M+H]+。1H NMR (300MHz, DMSO-d6) δ ppm 7.86 (s, 1H), 7.57-7.46 (m, 2H), 7.44-7.28 (m, 4H), 5.55 (s, 1H), 4.60 (br s, 2H), 4.39-4.09 (m, 3H), 3.28 (br s, 3H), 2.69 (q, J=7.5Hz, 2H), 1.19 (t, J= 7.5Hz, 3H).
Embodiment 55:
2- ((3,5- dicyano -4- ethyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides
By 2- [(the bromo- 3,5- dicyano -4- ethyl -2- pyridyl group of 6-) sulfanyl] -2- phenvl-acetamide (in embodiment Synthesis, 137mg, 0.34mmol are described in 6 steps 1) solution in tetrahydrofuran (5mL) with piperazine (350mg, 4.06mmol) processing of solution in tetrahydrofuran (5mL), it warms to dissolve, is then cooled down again in environment temperature.Gained is mixed Suspension stirs 20 minutes.The product mixtures are diluted with EtOAc (80mL), with water (3x 50mL), saturated sodium-chloride is washed simultaneously By obtaining 2- [(3,5- dicyano -4- ethyl -6- piperazine -1- base -2- pyridyl group) sulfane by the drying of Hydrophobic glass funnel Base] -2- phenvl-acetamide (123mg, 88% yield) is pale solid.LCMS m/z=407 [M+H]+。1H NMR (300MHz, DMSO-d6) δ ppm 7.91 (s, 1H), 7.62-7.46 (m, 2H), 7.44-7.30 (m, 4H), 5.52 (s, 1H), (3.79 br s, 4H), 3.43-3.37 (m, 1H), 2.88-2.67 (m, 6H), 1.20 (t, J=7.5Hz, 3H).
Embodiment 56:
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides
By 2- [(the bromo- 3,5- dicyano -4- ethyl -2- pyridyl group of 6-) sulfanyl] -2- phenvl-acetamide (in embodiment Synthesis, 467mg, 1.16mmol are described in 6 steps 1) solution N- methylhomopiperazin base in tetrahydrofuran (25mL) (0.36mL, 2.91mmol) is handled and is stirred in a nitrogen atmosphere 1.5 hours in environment temperature.It will be in the product mixtures dry method Sample is to SiO2(2g) and in SiO2Upper progress chromatogram purification (12g RediSep column, with 0-10%MeOH, 0-1%NH3/CH2Cl2It washes It is de-), obtain 2- [[3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) -2- pyridyl group] sulfane Base] -2- phenvl-acetamide (445mg, 88% yield) is white solid.LCMS m/z=435 [M+H]+。1H NMR (300MHz, DMSO-d6) δ ppm 7.91 (s, 1H), 7.54-7.45 (m, 2H), 7.43-7.29 (m, 4H), 5.51 (s, 1H), 4.01-3.79 (m, 4H), 2.84-2.55 (m, 6H), 2.26 (s, 3H), 2.08-1.79 (m, 2H), 1.21 (t, J=7.6Hz, 3H)。
Embodiment 57:
2- ((3,5- dicyano -4- ethyl -6- morpholino pyridine -2- base) sulfenyl) -2- phenyl-acetamides
By 2- [(the bromo- 3,5- dicyano -4- ethyl -2- pyridyl group of 6-) sulfanyl] -2- phenvl-acetamide (in embodiment Synthesis, 28mg, 0.07mmol are described in 6 steps 1) solution morpholine in tetrahydrofuran (1mL) and ethyl alcohol (0.5mL) (0.009mL, 0.1mmol) processing, while being stirred 1 hour in environment temperature.By the product mixtures dry method loading to SiO2 (0.8g), in SiO2(4g RediSep column, uses 0-5%MeOH/CH to upper progress chromatogram purification2Cl2Elution), then ground with ether Mill, obtain 2- [(3,5- dicyano -4- ethyl -6- morpholino -2- pyridyl group) sulfanyl] -2- phenvl-acetamide (19mg, 0.0466mmol, 67% yield), it is white solid.LCMS m/z=408 [M+H]+。1H NMR (300MHz, DMSO-d6)δ Ppm 7.90 (br s, 1H), 7.65-7.46 (m, 2H), 7.46-7.31 (m, 4H), 5.76-5.49 (m, 1H), 3.99-3.78 (m, 4H), 3.77-3.39 (m, 4H), 2.76 (q, J=7.3Hz, 2H), 1.21 (t, J=7.6Hz, 3H).
Embodiment 58:
2- [[6- (azetidine -1- base) -3,5- dicyano -4- ethyl -2- pyridyl group] sulfanyl] -2- phenyl-second Amide
By 2- [(the bromo- 3,5- dicyano -4- ethyl -2- pyridyl group of 6-) sulfanyl] -2- phenvl-acetamide (in embodiment Synthesis, 23mg, 0.06mmol are described in 6 steps 1) solution azetidine hydrochloride in tetrahydrofuran (1mL) The processing of (11.8mg, 0.13mmol) and triethylamine (0.02mL, 0.15mmol).Acquired solution is small in environment temperature stirring 16 When, dry method loading to SiO2(0.9g) and in SiO2(4g RediSep column, uses 0-5%MeOH/CH to upper progress chromatogram purification2Cl2 Elution), obtain 2- [[6- (azetidine -1- base) -3,5- dicyano -4- ethyl -2- pyridyl group] sulfanyl] -2- phenyl - Acetamide (19mg, 0.0503mmol, 86% yield), is white solid.LCMS m/z=376 [M-H]–。1H NMR (300MHz, DMSO-d6) δ ppm 7.86 (s, 1H), 7.55-7.39 (m, 2H), 7.39-7.25 (m, 4H), 5.55 (s, 1H), 4.56-4.28 (m, 4H), 2.68 (q, J=7.5Hz, 2H), 2.47-2.26 (m, 2H), 1.17 (t, J=7.6Hz, 3H).
Embodiment 59:
2- ((3,5- dicyano -4- ethyl -6- (4- oxo-piperidine -1- base) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine
By 2- [(the bromo- 3,5- dicyano -4- ethyl -2- pyridyl group of 6-) sulfanyl] -2- phenvl-acetamide (in embodiment Synthesis, 20mg, 0.05mmol are described in 6 steps 1) solution in tetrahydrofuran (1mL) is hydrated with 4- piperidone hydrochloride Object (11mg, 0.07mmol) and triethylamine (0.017mL, 0.12mmol) processing, are then stirred 72 hours in environment temperature.It should Product mixtures dry method loading is to SiO2(0.9g) and in SiO2(4g RediSep column, uses 0-15% to upper progress chromatogram purification MeOH/CH2Cl2Elution), obtain 2- ((3,5- dicyano -4- ethyl -6- (4- oxo-piperidine -1- base) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides (15mg, 0.0358mmol, 73%), are white solid.LCMS m/z=418 [M-H]–。1H NMR (300MHz, CD3OD with a drop of CDCl3) δ ppm 7.55-7.41 (m, 4H), 7.41-7.31 (m, 3H), 5.40 (s, 1H), 3.99-3.80 (m, 4H), 2.88 (q, J=7.6Hz, 2H), 1.95-1.77 (m, 4H), 1.30 (t, J=7.6Hz, 3H)。
Embodiment 60:
2- ((3,5- dicyano -4- ethyl -6- (1'- (2- hydroxyethyl)-[4,4'- joins piperidines] -1- base) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides
To 2- [(the bromo- 3,5- dicyano -4- ethyl -2- pyridyl group of 6-) sulfanyl] -2- phenvl-acetamide (in embodiment Synthesis, 25mg, 0.06mmol are described in 6 steps 1) and 2- [4- (4- piperidyl) -1- piperidyl] ethyl alcohol dihydrochloride Triethylamine (0.035mL, 0.25mmol) is added in the mixture in tetrahydrofuran (2mL) in (20mg, 0.07mmol).This is anti- Mixture is answered to stir 90 hours.The product mixtures are diluted with EtOAc (20mL), are washed with water (3x 20mL), salt water (25mL) It washs, filtered by Hydrophobic glass funnel and removes the solvent under reduced pressure.By the residue be dissolved in DMSO and with preparative HPLC it is pure Change, obtains 2- [[3,5- dicyano -4- ethyl -6- [4- [1- (2- hydroxyethyl) -4- piperidyl] -1- piperidyl] -2- pyridine Base] sulfanyl] -2- phenvl-acetamide (10mg, 30% yield) is white powder.LCMS m/z=531 [M-H]–。1H NMR (300MHz, DMSO-d6) δ ppm 8.22 (s, 1H), 7.92 (s, 1H), 7.57-7.46 (m, 2H), 7.44-7.28 (m, 4H), 5.53 (s, 1H), 4.62 (br d, J=11.6Hz, 2H), 3.74 (br s, 4H), 3.53 (br t, J=6.1Hz, 2H), 3.31-2.94 (m, 3H), 2.75 (q, J=7.3Hz, 2H), 2.48-2.36 (m, 1H), 2.27 (br s, 1H), 2.07 (br t, J =11.0Hz, 2H), 1.80 (br d, J=11.5Hz, 2H), 1.67 (br d, J=12.2Hz, 2H), 1.41 (br s, 1H), 1.25-1.15 (m, 5H).
Embodiment 61:
2- ((3,5- dicyano -6- ((3S, 5R) -3,5- lupetazin -1- base) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides
To 2- [(the bromo- 3,5- dicyano -4- ethyl -2- pyridyl group of 6-) sulfanyl] -2- phenvl-acetamide (in embodiment Synthesis, 30mg, 0.07mmol are described in 6 steps 1) and triethylamine (0.02mL, 0.15mmol) in tetrahydrofuran (2mL) Cis-DMP (9mg, 0.08mmol) is added in mixture.The reaction mixture is stirred 1.5 hours.It should Product mixtures are diluted with EtOAc (20mL), are washed with water (3x 20mL), saturated sodium-chloride (25mL), are leaked by Hydrophobic glass Bucket filters and removes the solvent under reduced pressure.It is dried in vacuo by obtained solid triturated under ether and at 50 DEG C, obtains 2- [[3,5- bis- Cyano -6- [(3R, 5S) -3,5- lupetazin -1- base] -4- ethyl -2- pyridyl group] sulfanyl] -2- phenvl-acetamide (27mg, 83% yield), is white solid.LCMS m/z=433 [M-H]–。1H NMR (300MHz, DMSO-d6)δppm 7.94 (s, 1H), 7.58-7.46 (m, 2H), 7.44-7.31 (m, 4H), 5.50 (s, 1H), 4.46 (br d, J=12.4Hz, 2H), 2.75 (q, J=7.4Hz, 4H), 2.67-2.53 (m, 3H), 1.20 (t, J=7.8Hz, 3H), 1.10-0.96 (m, 6H).
Embodiment 62:
2- ((6- (8- azabicyclo [3.2.1] oct-3-yl (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides
Step 1:(1R, 3r, 5S) -3- (((benzyl oxygroup) carbonyl) amino) -8- azabicyclo [3.2.1] octane -8- first Tert-butyl acrylate
By (1R, 3r, 5S) -3- amino -8- azabicyclo [3.2.1] octane -8- t-butyl formate (1g, 4.42mmol) It is dissolved in methylene chloride (15mL) and triethylamine (1.23mL, 8.84mmol) is added.The solution is cooled to 0 DEG C and chloro-carbonic acid is added dropwise Benzyl ester (0.662mL, 4.64mmol).The reaction is warmed to room temperature overnight.The solvent is evaporated and passes through surplus materials Silica gel chromatography (10-75% ethylacetate-hexane) obtains (1R, 3r, 5S) -3- (((benzyl oxygroup) carbonyl) amino) - 8- azabicyclo [3.2.1] octane -8- t-butyl formate (1.3g, 82%) .LCMS m/z=383 [M+Na]+。
Step 2:(1R, 3r, 5S) -3- (((benzyl oxygroup) carbonyl) (methyl) amino) -8- azabicyclo [3.2.1] is pungent Alkane -8- t-butyl formate
By (1R, 3r, 5S) -3- (((benzyl oxygroup) carbonyl) amino) -8- azabicyclo [3.2.1] octane -8- formic acid uncle Butyl ester (700mg, 1.94mmol) is dissolved in tetrahydrofuran (15mL) and n,N-Dimethylformamide (5mL), and sodium hydride is then added (51.5mg, 2.039mmol).The solution is stirred 15 minutes.Bubbling stop, then be added dropwise iodomethane (0.158mL, 2.52mmol).The reaction is stirred 2 hours at 25 DEG C.The solvent is evaporated and the thick material is dissolved in ethyl acetate, is washed with water It washs and dry with sodium sulphate.By the thick matter compound with silica gel chromatography (10-75% ethylacetate-hexane), obtain (1R, 3r, 5S) -3- (((benzyl oxygroup) carbonyl) (methyl) amino) -8- azabicyclo [3.2.1] octane -8- t-butyl formate (600mg, 83%).LCMS m/z=397 [M+Na]+。
Step 3:(1R, 3r, 5S) -3- (methylamino) -8- azabicyclo [3.2.1] octane -8- t-butyl formate
By (1R, 3r, 5S) -3- (((benzyl oxygroup) carbonyl) (methyl) amino) -8- azabicyclo [3.2.1] octane -8- T-butyl formate (350mg, 0.935mmol) is dissolved in ethyl alcohol (20mL) and 10%Pd/C (5mg) is added and by the reaction mixture It is exposed to 30psi hydrogen 3 hours.The mixture is filtered and the filtrate is concentrated to get (1R, 3r, 5S) -3- (methylamino) - 8- azabicyclo [3.2.1] octane -8- t-butyl formate (215mg, 96%).LCMS m/z=241 [M+H]+。
Step 4:3- ((the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) (methyl) amino) -8- azabicyclo [3.2.1] octane -8- t-butyl formate
By chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in 3 step 2 of embodiment, 200mg, It 0.885mmol) is dissolved in tetrahydrofuran (20mL) and 3- (methylamino) -8- azabicyclo [3.2.1] octane -8- formic acid uncle is added Then diisopropylethylamine (0.308mL, 1.77mmol) is added in butyl ester (213mg, 0.885mmol).The solution is stirred at 40 DEG C It mixes 4 hours.The reaction is concentrated, which is dissolved in water and (135mg required product) is collected by filtration in insoluble solids. The filtrate is concentrated to get solid, by it by silica gel chromatography (20-75% ethylacetate-hexane), obtains another The required product of 115mg.Two parts are merged, 3- ((chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-) (methyl) ammonia is obtained Base) -8- azabicyclo [3.2.1] octane -8- t-butyl formate (250mg, 66%) .LCMS m/z=452 [M+Na]+。
Step 5: thioacetic acid S- (2- amino -2- oxo -1- phenylethyl) ester
Thioacetic acid potassium is added in the solution in acetone (120mL) to the chloro- 2- phenvl-acetamide (6g, 35mmol) of 2- (4.08g, 36mmol) and the reaction is stirred and is heated to reflux 2 hours in a nitrogen atmosphere.It is the mixture is cooling and should Solvent under reduced pressure removes.Obtained solid is allocated between water (200mL) and EtOAc (200mL), each phase is filtered and separate.To have Machine is mutually washed with salt water (200mL), is filtered by Hydrophobic glass funnel, which removes.Obtained solid is ground with ether Mill, filtering, is washed and is air-dried with the ether of minimum, obtain thioacetic acid S- (2- amino -2- oxo -1- phenylethyl) ester (2.8g, 38% yield), is cream-coloured powder.LCMS m/z=208.0 [M-H]–。
Step 6:2- ((6- (8- azabicyclo [3.2.1] oct-3-yl (methyl) amino) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) sulfenyl) -2- phenyl-acetamides
By thioacetic acid S- (2- amino -2- oxo -1- phenylethyl) ester (in 3 step 5 of embodiment describe synthesis, 120mg, 0.575mmol) it is dissolved in ethyl alcohol (10mL) and NaBH is added4(27.2mg, 0.719mmol).The solution is stirred at 70 DEG C It mixes 6 minutes.The reaction is cooling and by 3- ((the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) (methyl) amino) -8- nitrogen Miscellaneous bicyclic [3.2.1] octane -8- t-butyl formate (206mg, 0.479mmol) is molten in n,N-Dimethylformamide (15mL) Liquid is added and heats the reaction mixture 4 minutes at 70 DEG C.The reaction mixture is concentrated under reduced pressure and by the crude material Material passes through silica gel chromatography (12-70% ethylacetate-hexane).By the material of the purifying be dissolved in methylene chloride (5mL) and Simultaneously the reaction is stirred at room temperature 1 hour for trifluoroacetic acid (5mL).The reaction is concentrated under reduced pressure.Remaining residue is molten It is washed in methylene chloride and with saturated sodium bicarbonate aqueous solution.Organic layer is concentrated, 2- ((6- (8- azabicyclo is obtained [3.2.1] oct-3-yl (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides (63mg, 28%).LCMS m/z=461 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 1.22 (t, J=7.58Hz, 3H) 1.57 (t, J=11.75Hz, 2H) 1.78-2.00 (m, 4H) 2.18-2.37 (m, 2H) 2.78 (q, J=7.58Hz, 2H) 3.16 (s, 4H) (3.86 br.s., 2H) 5.00 (t, J=7.83Hz, 1H) 5.49 (s, 1H) 7.34-7.48 (m, 3H) 7.54 (d, J=7.07Hz, 2H) 7.66 (br.s., 1H) 8.12 (s, 1H).
Embodiment 63:
2- ((3,5- dicyano -4- cyclopropyl -6- (2- (hydroxymethyl) morpholino) pyridine -2- base) sulfenyl) -2- phenyl Acetamide
The chloro- 4- cyclopropyl -6- of step 1:2- (2- (hydroxymethyl) morpholino) pyridine -3,5- dimethoxy nitrile
To chloro- 4- cyclopropyl pyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in 3 step 2 of embodiment, 237mg, 1mmol) in the solution in n,N-Dimethylformamide (10mL) be added morpholine -2-base methanol (117mg, 1mmol), then plus Enter Et3N (0.14mL, 1mmol).The reaction is stirred at room temperature 30 minutes, is then diluted with water (20mL).By the solid of precipitation It is collected by filtration and dries in an oven, obtain the chloro- 4- cyclopropyl -6- of 2- (2- (hydroxymethyl) morpholino) pyridine -3,5- Dimethoxy nitrile (280mg, 88%).LCMS m/z=319 [M+H]+。
Step 2:2- ((3,5- dicyano -4- cyclopropyl -6- (2- (hydroxymethyl) morpholino) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides
By the chloro- 4- cyclopropyl -6- of 2- (2- (hydroxymethyl) morpholino) pyridine -3,5- dimethoxy nitrile (280mg, 0.88mmol) stirred with the solution of thioacetic acid potassium (121mg, 1.06mmol) in n,N-Dimethylformamide (9mL) in room temperature Mix 30 minutes, be then added methanesulfonic acid 2- amino -2- oxo -1- phenylethylester (describe synthesis in 3 step 5 of embodiment, 242mg, 1.06mmol) and Et3N (0.25mL, 1.76mmol).The reaction mixture is stirred at room temperature overnight, water is then used (20mL) dilution.The solid by filtration of precipitation is collected and is passed through silica gel chromatography (MeOH:DCM1:20), 2- is obtained ((3,5- dicyano -4- cyclopropyl -6- (2- (hydroxymethyl) morpholino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides (102mg, 26%) .LCMS m/z=450 [M+H]+。1H NMR (400MHz, CDCl3) δ ppm 7.50-7.33 (m, 5H), 6.75 (d, J=22.0Hz, 1H), 5.91 (d, J=38.7Hz, 1H), 5.31 (d, J=7.3Hz, 1H), 4.73 (dd, J=35.2, 13.5Hz, 1H), 4.45 (t, J=14.5Hz, 1H), 4.02 (d, J=11.5Hz, 1H), 3.77-3.56 (m, 4H), 3.52- 3.42 (m, 1H), 3.07-2.95 (m, 1H), 2.19 (br s, 1H), 2.13-2.05 (m, 1H), 1.35-1.26 (m, 2H), 1.22-1.11 (m, 2H).
Embodiment 64:
(R) -2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides
By 2- [[3,5- dicyano -6- (dimethylamino) -4- ethyl -2- pyridyl group] sulfanyl] -2- phenyl-acetyl In the boiling methanol (9mL) for 300 volumes that amine (describing synthesis, 496mg in 3 step 6 of embodiment) is dissolved in the part 30mg simultaneously (30mm x 250mm) is split on Lux-2cellulose, 5 microns of columns with chiral HPLC and with 100% methanol (50mL/min) Elution.It is collected into the reaction mixture that total amount is about 900mL, is concentrated it to dry.The solid is dried extremely under 40 DEG C of high vacuum Final constant weight obtains (R) -2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide (232mg), is white solid.LCMS m/z=366 [M+H]+.Chiral HPLC: > 99.8%ee chiral purity Degree.Optical activity: -316 ° (C=0.2, chloroform-d, 21 DEG C).1H NMR(DMSO-d6) δ ppm 7.91 (s, 1H), 7.52 (d, J= 7.1Hz, 2H), 7.29-7.42 (m, 4H), 5.59 (s, 1H), 3.34 (s, J=7.8Hz, 6H), 2.76 (q, J=7.4Hz, 2H), 1.20 (t, J=7.6Hz, 3H).
Embodiment 64 (a) another kind route
(R) -2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides
It (is described in 418 step 3 of embodiment to (S) -4- toluenesulfonic acid 2- amino -2- oxo -1- phenylethylester Synthesis, 65.7mg, 0.215mmol), 2- (dimethylamino) -4- ethyl -6- mercaptopyridine -3,5- dimethoxy nitrile is (in embodiment Synthesis, 50mg, 0.215mmol are described in 92 steps 3) three second are added in the solution in n,N-Dimethylformamide (1mL) Amine (0.060mL, 0.430mmol).The reaction is stirred at room temperature 6 hours.The mixture is poured into H2O (5mL) simultaneously stirs 10 Minute, then filtering and with other H2O (5mL) washing, is dried overnight in pump, obtains the crude product of 67mg.By the sample With the purification by flash chromatography (CHCl of 0-100%EtOAc3Solution).The product fraction is concentrated, then by residue DCM It grinds and filters, obtain (R) -2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl Acetamide (40mg, 0.109mmol, 51% yield), is white solid.LCMS (ES) m/z=388.0 [M+Na]+。1H NMR (DMSO-d6) δ ppm 7.93 (s, 1H), 7.46-7.56 (m, 2H), 7.27-7.44 (m, 4H), 5.59 (s, 1H), 3.32-3.36 (m, 6H), 2.76 (q, J=7.4Hz, 2H), 1.21 (t, J=7.5Hz, 3H).Chiral HPLC indicates 99.5%ee.
Embodiment 65
(R) -2- [(3,5- dicyano -4- ethyl -6- morpholino -2- pyridyl group) sulfanyl] -2- phenvl-acetamide
The chloro- 4- ethyl -6- morpholino pyridine -3,5- dimethoxy nitrile of step 1:2-
In room temperature, to chloro- 4- EthylPyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (in 3 step 2 of embodiment describe synthesis, 1.0g, 4.42mmol) addition morpholine (0.386mL, 4.42mmol) in the solution in tetrahydrofuran (25mL).By the mixture Stirring 15 minutes, is then added the morpholine (0.386mL, 4.42mmol) of 1 additional equivalent.Then the mixture is stirred 75 points Then the additional morpholine of 0.5 equivalent (0.19mL, 2.21mmol) is added in clock.After 30 minutes, which is filtered, it will The solid of collection is washed with tetrahydrofuran (2x 25mL) and the filtrate decompression is concentrated.Obtained solid is dissolved in ethyl acetate (25mL) is filtered by Hydrophobic glass funnel, dry method loading to SiO2, then pass through silica gel chromatography (0-30% acetic acid Ethyl ester/hexane), chloro- 4- ethyl -6- morpholino-pyridine -3, the 5- dimethoxy nitrile (926mg, 76%) of 2- is obtained, is white powder. LCMS m/z=275 [M-H]–。
Step 2:2- ((3,5- dicyano -4- ethyl -6- morpholino pyridine -2- base) sulfenyl) -2- phenyl-acetamides
At 70 DEG C, sodium borohydride (114mg, 3.01mmol) continues to add within 5 minutes thioacetic acid S- (2- ammonia in batches Base -2- oxo -1- phenylethyl) ester (describing synthesis, 0.46g, 2.2mmol in 3 step 5 of embodiment) is at ethyl alcohol (20mL) In solution.The reaction mixture is stirred 15 minutes at 70-80 DEG C.The reaction is removed into heat source and the chloro- 4- ethyl-of 2- is added 6- morpholino-pyridine -3,5- dimethoxy nitrile (590mg, 2.13mmol).Gained mixture is heated 15 minutes at 80 DEG C, is cooled to Room temperature, it is then further cooling with ice water bath.The solid by filtration that will be present is collected and is used ice-cold ethyl alcohol (5mL), cold Ethanol water (50% aqueous solution, 10mL), water (2x 15mL) are washed and are dried in vacuo.Then by the solid ether/hexane The washing of (1:1,10mL), hexane (10mL) is simultaneously dried in vacuo at 50 DEG C, obtains racemic 2- [(3,5- dicyano -4- ethyls - 6- morpholino -2- pyridyl group) sulfanyl] -2- phenvl-acetamide (542mg, 62%) is white solid.LCMS m/z= 408[M+H]+。
Step 3:(R) -2- [(3,5- dicyano -4- ethyl -6- morpholino -2- pyridyl group) sulfanyl] -2- phenyl-second Amide
By racemic 2- [(3,5- dicyano -4- ethyl -6- morpholino -2- pyridyl group) sulfanyl] -2- phenyl-second Amide (232mg) is dissolved in (8mL) boiling methanol of 400 volumes of the part 20mg and filters.The sample is passed through into chirality HPLC, (30mm x 250mm) is split using Chiral, CC4,5 microns of columns of Chromega, is eluted with 100% methanol (42mL/min). It is collected into the reaction mixture that total amount is about 400mL, concentrates it to substantially dry, obtains white slurry.By this by the slurries filtration, It is with the methanol elution of minimum and dry to final constant weight under 40 DEG C of high vacuum, obtain (R) -2- [(3,5- dicyanos - 4- ethyl -6- morpholino -2- pyridyl group) sulfanyl] -2- phenvl-acetamide (102mg) is white solid.LCMS m/z= 408[M+H]+.99.2%ee chiral purity.Optical activity: -285 ° of (C=0.20, DMSO-d6, 23 DEG C).1H NMR(DMSO-d6)δ Ppm7.89 (s, 1H), 7.47-7.56 (m, 2H), 7.28-7.44 (m, 4H), 5.52 (s, 1H), 3.90 (t, J=4.7Hz, 4H), 3.60-3.75 (m, 4H), 2.77 (q, J=7.6Hz, 2H), 1.21 (t, J=7.6Hz, 3H).
Embodiment 66
N- (4- ((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- base sulfenyl) Methyl) benzyl) acetamide trifluoroacetate
The chloro- 4- ethyl -6- of step 1:2- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -3,5- dimethoxy nitrile
At 0 DEG C, by solution of 4- (pyrrolidin-1-yl) piperidyl (1.5g, 9.72mmol) in methylene chloride (30mL) Add to chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in 3 step 2 of embodiment, 2.198g, 9.72mmol) and triethylamine (1.355mL, 9.72mmol) is in the mixture in methylene chloride (30mL).By gained mixture It is warmed to 25 DEG C and stirs 12 hours.The reaction mixture water (30mL) is distributed and separates each layer.Simultaneously by organic layer concentration By remaining residue by silica gel chromatography (petroleum ether: ethyl acetate 2:1), the chloro- 4- ethyl -6- (4- (pyrrole of 2- is obtained Cough up alkane -1- base) piperidin-1-yl) pyridine -3,5- dimethoxy nitrile (3.6g) .LCMS m/z=344 [M+H]+。
Step 2:4- (amino methyl) phenyl) methanol
At 0 DEG C, it is added in the cooling suspension in tetrahydrofuran (50mL) to lithium aluminium hydride reduction (5.79g, 153mmol) Tetrahydrofuran (50mL) solution of 4- formylbenzonitrile (5g, 38.1mmol).Gained mixture is stirred at room temperature overnight, then It is cooled to 0 DEG C and is handled with sodium hydrate aqueous solution (5N, 32.1mL).Then gained mixture filtered and the filtrate is true Sky concentration, obtains (4- (amino methyl) phenyl) methanol (4.5g, 73%), is white solid.LCMS m/z=138.1 [M+ H]+。
Step 3:N- (4- (hydroxymethyl) benzyl) acetamide
By (4- (amino methyl) phenyl) methanol (0.96g, 7.00mmol) and acetic anhydride (7.14g, 70.0mmol) in second Solution in sour (20mL) stirs 6 hours in 110 DEG C of sealed tubes.After being cooled to room temperature, which is concentrated in vacuo.This is residual Excess is diluted with methanol (15mL), is handled and is stirred at room temperature overnight with lithium hydroxide (0.838g, 35.0mmol).By the reaction It is concentrated and surplus materials is allocated between ethyl acetate (50mL) and water (25mL).It separates each layer and organic layer is saturated chlorine Change sodium solution (25mL) washing, with sodium sulphate drying and is concentrated in vacuo, obtains the crude product.Raw product is passed through into silicagel column color Spectrum purifying (methylene chloride: methanol 15:1), obtains N- (4- (hydroxymethyl) benzyl) acetamide (0.23g, 17%)1H NMR (400MHz, DMSO-d6) δ ppm 8.32 (br.s, 1H), 7.23 (dd, J=24.5,8.0Hz, 4H), 5.14 (t, J=5.7Hz, 1H), 4.47 (d, J=5.6Hz, 2H), 4.22 (d, J=5.9Hz, 2H), 1.86 (s, 3H).
Step 4:N- (4- ((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- base Sulfenyl) methyl) benzyl) acetamide trifluoroacetate
At 0 DEG C, to N- (4- (hydroxymethyl) benzyl) acetamide (180mg, 1.004mmol) and triethylamine (305mg, Methane sulfonyl chloride (173mg, 1.507mmol) 3.01mmol) is added in the solution in tetrahydrofuran (8mL).Gained is mixed Object is stirred 0.5 hour at 0 DEG C and is stirred for 1 hour in room temperature.The reaction is allocated in ethyl acetate (50mL) and water (25mL) Between.Each layer is separated, organic layer is washed with saturated sodium chloride solution (25mL), with sodium sulphate drying and is concentrated in vacuo, and is obtained thick Methanesulfonic acid 4- (acetylamino methyl) benzyl ester (0.27g) of system, is brown solid.To the chloro- 4- ethyl -6- (4- (pyrroles of 2- Alkane -1- base) piperidin-1-yl) pyridine -3,5- dimethoxy nitrile (0.361g, 1.049mmol) is in n,N-Dimethylformamide (10mL) Solution in be added thioacetic acid potassium (0.180g, 1.574mmol).The reaction mixture is stirred at room temperature 2 hours, is then used Potassium carbonate (0.145g, 1.049mmol) processing.After being stirred at room temperature 1 hour, crude methanesulfonic acid 4- (acetylamino first is added Base) benzyl ester (0.27g, 1.049mmol) and the mixture is stirred at room temperature overnight.The reaction is concentrated in vacuo, then will The residue is allocated between ethyl acetate (50mL) and water (25mL).Separate each layer.By organic layer saturated sodium chloride solution (25mL) washing with sodium sulphate drying and is concentrated in vacuo, obtains raw product, be brown solid.It prepared by raw product Type-HPLC purifying, obtains N- (4- (((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- Base) sulfenyl) methyl) benzyl) acetamide trifluoroacetate (120mg) .LCMS m/z=503 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 1.22 (t, J=7.6Hz, 3H), 1.66 (dd, J=21.2,12.2Hz, 2H), 1.87 (s, 5H), 2.02 (s, 2H), 2.21 (d, J=10.7Hz, 2H), 2.79 (q, J=7.5Hz, 2H), 3.25-3.04 (m, 4H), 3.60-3.40 (m, 3H), 4.22 (d, J=5.9Hz, 2H), 4.50 (s, 2H), 4.61 (d, J=13.6Hz, 2H), 7.22 (d, J=8.0Hz, 2H), 7.37 (d, J=8.0Hz, 2H), 8.37 (t, J=5.7Hz, 1H), 9.92 (s, 1H).
Embodiment 67
2- { [3,5- dicyano -4- ethyl -6- (5- methyl-1,4- Diazesuberane -1- base) pyridine -2- base] sulfane Base } -2- phenyl-acetamides
To 2- [(the bromo- 3,5- dicyano -4- ethyl -2- pyridyl group of 6-) sulfanyl] -2- phenvl-acetamide (in embodiment Synthesis, 30mg, 0.07mmol are described in 6 steps 1) and triethylamine (0.02mL, 0.16mmol) in tetrahydrofuran (2mL) 5- methyl-[Isosorbide-5-Nitrae] diazacyclo heptantriene (9mg, 0.08mmol) is added in solution.The mixture is stirred 17 in environment temperature Hour.The product mixtures are diluted with water (7.5mL), filtering is washed with water (2x 10mL) and is dried in vacuo at 50 DEG C, obtained To 2- [[3,5- dicyano -4- ethyl -6- (5- methyl-1,4- Diazesuberane -1- base) -2- pyridyl group] sulfanyl] -2- Phenvl-acetamide is the complex mixture (24mg, 74% yield) of diastereoisomer, is pale solid.1H NMR (300MHz, DMSO-d6) δ ppm 7.91 (br s, 1H), 7.54-7.44 (m, 2H), 7.44-7.28 (m, 4H), 5.52 (d, J= 2.3Hz, 1H), 4.19-4.03 (m, 1H), 4.01-3.85 (m, 1H), 3.84-3.58 (m, 2H), 3.22-3.03 (m, 1H), 2.89 (br d, J=10.5Hz, 1H), 2.84-2.69 (m, 3H), 1.89 (br s, 1H), 1.45 (br d, J=13.7Hz, 1H), 1.36 (s, 1H), 1.28-1.09 (m, 3H), 1.09-0.87 (m, 3H).LCMS m/z=433 [M-H]–.
Embodiment 68
2- (4- (amino methyl) benzyl sulfenyl) -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -3, 5- dimethoxy nitrile 2,2,2- trifluoro-acetate
The chloro- 4- ethyl -6- of step 1:2- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -3,5- dimethoxy nitrile
At 0 DEG C, solution of 4- (pyrrolidin-1-yl) piperidines (1.5g, 9.72mmol) in methylene chloride (30mL) is added To chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile (describing synthesis, 2.19g, 9.72mmol in embodiment 3, step 2) of 2,6- bis- With triethylamine (1.355mL, 9.72mmol) in the mixture in methylene chloride (30mL).The mixture is warmed to 25 DEG C simultaneously Stirring 12 hours.The mixture is washed with water (30mL), organic phase is concentrated and column chromatography (PE:EA=2:1) is used to purify, is obtained To the chloro- 4- ethyl -6- of 2- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -3,5- dimethoxy nitrile (3.6g).LCMS m/z= 344.1[M+H]+。
Step 2:(4- (amino methyl) phenyl) methanol
At 0 DEG C, to LiAlH44- first is added in (5.79g, 153mmol) in the cooling suspension in tetrahydrofuran (50mL) Solution of the acyl group benzonitrile (5g, 38.1mmol) in tetrahydrofuran (50mL).Gained mixture is stirred at room temperature overnight, then It cools down and sodium hydrate aqueous solution (5N, 32.1mL) is used to handle at 0 DEG C.Gained mixture is filtered, and concentrated under reduced pressure to give (4- (amino methyl) phenyl) methanol (4.5g, 27.9mmol, 73% yield) is gray solid.LCMS m/z=138.1 [M+H ]+。
Step 3:4- (hydroxymethyl) benzylcarbamate tert-butyl ester
By (4- (amino methyl) phenyl) methanol (1g, 7.29mmol) and di-tert-butyl dicarbonate (1.59g, 7.29mmol) mixture in methylene chloride (30mL) is stirred at room temperature overnight, and is then concentrated under reduced pressure and is added raw product Into silicagel column and with methylene chloride: ethyl acetate (1:1) elutes, and obtains 4- (hydroxymethyl) benzylcarbamate tert-butyl ester (0.8g, 2.28mmol, 31% yield), is white solid.1H NMR (400MHz, DMSO-d6) δ ppm 7.37 (s, 1H), 7.22 (dd, J=27.8,8.0Hz, 4H), 5.13 (t, J=5.7Hz, 1H), 4.46 (d, J=5.7Hz, 2H), 4.10 (d, J= 6.1Hz, 2H), 1.36 (s, 9H).
Step 4:4- ((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- base sulphur Base) methyl) the benzylcarbamate tert-butyl ester
At 0 DEG C, to 4- (hydroxymethyl) the benzylcarbamate tert-butyl ester (350mg, 1.47mmol) and triethylamine Methane sulfonyl chloride (253mg, 2.212mmol) is added in the solution in tetrahydrofuran (10mL) in (448mg, 4.42mmol).It will Gained mixture is stirred 0.5 hour at 0 DEG C and is stirred at room temperature 1 hour, is then diluted with ethyl acetate (50mL).This is organic It is mutually washed with water (25mL) and saturated brine (25mL), with sodium sulphate drying and is evaporated in vacuo, obtains crude methanesulfonic acid 4- (((tertbutyloxycarbonyl) amino) methyl) benzyl ester (500mg), is brown solid.To the chloro- 4- ethyl -6- (4- (pyrroles of 2- Alkane -1- base) piperidin-1-yl) pyridine -3,5- dimethoxy nitrile (545mg) in the solution in N,N-dimethylformamide (15mL) plus Enter thioacetic acid potassium (272mg, 2.37mmol).The mixture is stirred at room temperature 2 hours, then with potassium carbonate (438mg, 3.17mmol) processing.Gained mixture is stirred at room temperature 1 hour, then with crude methanesulfonic acid 4- (((tertbutyloxycarbonyl) Amino) methyl) processing of benzyl ester (500mg) brown solid.The mixture is stirred at room temperature overnight, is then concentrated under reduced pressure.It will The residue is diluted with ethyl acetate (100mL).Organic phase is washed with water (50mL) and saturated brine (50mL), uses sodium sulphate It dries and is evaporated in vacuo, obtain crude 4- ((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyrrole Pyridine -2- base sulfenyl) methyl) the benzylcarbamate tert-butyl ester (0.8g), be brown solid, be used in next step without into The purifying of one step.LCMS m/z=561.2 [M+H]+。
Step 6:2- ((4- (amino methyl) benzyl) sulfenyl) -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) Pyridine -3,5- dimethoxy nitrile, trifluoroacetate
In room temperature, to crude 4- (((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyrrole Pyridine -2- base) sulfenyl) methyl) the benzylcarbamate tert-butyl ester (0.78g) is added 2,2 in the solution in methylene chloride (20mL), 2- trifluoroacetic acid (1.58g, 13.9mmol).Gained mixture is stirred at room temperature overnight, is then concentrated under reduced pressure and by crude production Object is purified with preparative-HPLC, obtains 2- ((4- (amino methyl) benzyl) sulfenyl) -4- ethyl -6- (4- (pyrrolidin-1-yl) Piperidin-1-yl) pyridine -3,5- dimethoxy nitrile, trifluoroacetate (150mg, 0.261mmol), is white solid.LCMS m/z= 460.7[M+H]+。1H NMR (400MHz, DMSO) δ ppm 10.30 (s, 1H), 8.28 (s, 2H), 7.45 (q, J=8.2Hz, 4H), 4.62 (d, J=13.5Hz, 2H), 4.53 (s, 2H), 4.03 (q, J=5.6Hz, 2H), 3.63-3.41 (m, 3H), 3.25- 3.05 (m, 4H), 2.79 (q, J=7.5Hz, 2H), 2.22 (d, J=10.4Hz, 2H), 2.02 (s, 2H), 1.93-1.81 (m, 2H), 1.70 (td, J=12.0,8.9Hz, 2H), 1.22 (t, J=7.6Hz, 3H).
Embodiment 69
4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) methyl) the benzylcarbamate tert-butyl esterStep 1:4- ethyl -2- sulfydryl -6- (4- methyl-1,4- Diazesuberane -1- Base) pyridine -3,5- dimethoxy nitrile
At -20 DEG C, (conjunction is described in embodiment 3, step 2 to chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- 1- methyl-1 is added in the solution in ethyl alcohol (20mL) at 3.0g, 13.27mmol), 4- Diazesuberane (1.82mL, 14.66mmol) the solution in ethyl alcohol (20mL).Then the reaction mixture is stirred 2 hours at -20 DEG C.Then anti-to this It answers and thioacetic acid potassium (2.3g, 20.14mmol) and triethylamine (4.62mL, 33.2mmol) is added in mixture.Then this is anti- It answers mixture to be warmed to 20 DEG C and monitors process with LCMS simultaneously in mutually synthermal stirring.It is after 20 DEG C are stirred overnight, this is non- Homogeneous reaction mixture filters and washs solid with ethyl alcohol and ether.The solid is dry in vacuum drying oven, obtain 4- second Base -2- sulfydryl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -3,5- dimethoxy nitrile (5.2g, 130%).LCMS m/ Z=302 [M+H]+。
Step 2:4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) methyl) the benzylcarbamate tert-butyl ester
At 0 DEG C, to 4- ethyl -2- sulfydryl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -3,5- diformazan Nitrile (500mg, 1.659mmol) and triethylamine (0.185mL, 1.327mmol) are mixed in n,N-Dimethylformamide (4.0mL) Addition 4- (bromomethyl) the benzylcarbamate tert-butyl ester (398mg, 1.327mmol) in suspension is in n,N-Dimethylformamide Solution in (4.0mL).Then the reaction mixture is for the weekend in 0 DEG C of stirring, the reaction mixture ethyl acetate is dilute It releases and washs the mixture with water (3x).Then combined aqueous layer with ethyl acetate (1x) is stripped.By the organic of merging Layer is washed with saturated brine, and dry (magnesium sulfate) is simultaneously concentrated, and obtains required raw product.By the required crude product positive Chromatogram purification (Biotage Isolera, 25g SNAP ULTRA column, methylene chloride/methanol 0-5%), obtains 4- (((3,5- bis- Cyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) methyl) benzylcarbamate The tert-butyl ester (404mg, 47%) is orange glue.LCMS m/z=521 [M+H]+。1H NMR (400MHz, DMSO-d6)δppm 7.39 (t, J=6.08Hz, 1H), 7.34 (d, J=8.11Hz, 2H), 7.19 (d, J=8.11Hz, 2H), 4.47 (s, 2H), 4.09 (d, J=5.83Hz, 2H), 3.81-3.94 (m, 4H), 2.78 (q, J=7.60Hz, 2H), 2.62-2.69 (m, 2H), 2.24 (s, 3H), 1.87-1.97 (m, 2H), 1.39 (s, 9H), 1.22 (t, J=7.60Hz, 3H), (2H is covered by DMSO).
Embodiment 70
4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) methyl) benzamide
In room temperature, to 4- ethyl -2- sulfydryl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -3,5- diformazan Nitrile (synthesis, 60mg, 0.199mmol are described in embodiment 69, step 1) and 4- (bromomethyl) benzamide (42mg, Triethylamine (0.055mL, 0.398mmol) 0.196mmol) is added in the suspension in n,N-Dimethylformamide (1.0mL). Then the reaction mixture is stirred at room temperature overnight.The reaction mixture is filtered and the filtrate is purified with reversed-phase HPLC (Gilson, 30mm x 50mm Gemini column, NH4OH modifying agent), the required product purified.Separated material is used Reversed-phase HPLC repurity (Gilson, 30mm x 50mm Gemini column, NH4OH modifying agent), obtain 4- (((3,5- dicyanos- 4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) methyl) benzamide (8mg, 9%), It is white solid.LCMS m/z=435 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm7.96 (br.s., 1H), (7.65-7.90 m, J=8.36Hz, 2H), 7.42-7.65 (m, J=8.36Hz, 2H), 7.37 (s, 1H), 4.55 (s, 2H), 3.81-3.90 (m, 4H), 2.78 (q, J=7.60Hz, 2H), 2.55-2.62 (m, 2H), 2.43-2.48 (m, 2H), 2.21 (s, 3H), 1.84-1.98 (m, 2H), 1.22 (t, J=7.60Hz, 3H).
Embodiment 71
2- ((4- (amino methyl) benzyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyrrole Pyridine -3,5- dimethoxy nitrile dihydrochloride
By 4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) the benzylcarbamate tert-butyl ester (synthesis, 393mg, 0.755mmol are described in embodiment 69, step 2) exists Suspension in the dioxane of HCl (4M, 4mL, 16.0mmol) is stirred at room temperature 2 hours.Then by the reaction mixture Concentration.Resulting materials are suspended in ethyl acetate, are ultrasonically treated.The solid is filtered, is then washed with ethyl acetate and ether. The solid is dry in vacuum drying oven, obtain 2- ((4- (amino methyl) benzyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -3,5- dimethoxy nitrile dihydrochloride (288mg, 77% yield) is pale pink solid.LCMS M/z=421 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 11.09 (br.s., 1H), 8.42 (br.s., 3H), 7.42- 7.50 (m, 4H), 4.52 (d, J=1.77Hz, 2H), 4.31 (d, J=12.42Hz, 1H), 3.83-4.04 (m, 4H), 3.43- 3.53 (m, 2H), 3.14-3.32 (m, 2H), 2.82 (q, J=7.44Hz, 2H), 2.73 (br.s., 3H), 2.22 (br.s., 1H), 1.24 (t, J=7.60Hz, 3H) (2H is covered by DMSO).
Embodiment 72
2- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) phenyl) acetic acid
At 0 DEG C, to 4- ethyl -2- sulfydryl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -3,5- diformazan Nitrile (synthesis, 75mg, 0.249mmol are described in embodiment 69, step 1) and triethylamine (0.062mL, 0.448mmol) exist 2- (4- (bromomethyl) phenyl) acetic acid (46mg, 0.201mmol) is added in suspension in n,N-Dimethylformamide (0.5mL) Solution in N,N-dimethylformamide (0.5mL).After 0 DEG C is stirred overnight, which is warmed to room temperature, mistake It filters and purifies (Gilson, 30mm x 50mm Gemini column, NH with reversed-phase HPLC4OH modifying agent), obtain 2- (4- (((3,5- Dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) methyl) phenyl) acetic acid (48mg, 43% yield) is orange glue.LCMS m/z=450 [M+H]+。1H NMR (400MHz, DMSO-d6)δppm 7.26 (d, J=8.11Hz, 2H), 7.16 (d, J=8.11Hz, 2H), 4.45 (s, 2H), 3.82-3.96 (m, 4H), 3.30 (s, 2H), 2.78 (q, J=7.60Hz, 2H), 2.60-2.70 (m, 2H), 2.24 (s, 3H), 1.84-1.99 (m, 2H), 1.22 (t, J= 7.60Hz, 3H), (2H is covered by DMSO, and sour H is not observed)
Embodiment 73
4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) methyl) benzoic acid
At 0 DEG C, to 4- ethyl -2- sulfydryl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -3,5- diformazan Nitrile (synthesis, 75mg, 0.249mmol are described in embodiment 69, step 1) and triethylamine (0.062mL, 0.448mmol) exist 4- (bromomethyl) benzoic acid (43mg, 0.200mmol) is added in suspension in n,N-Dimethylformamide (0.5mL) in N, N- Solution in dimethylformamide (0.5mL).After 0 DEG C is stirred overnight, which is warmed to room temperature, filtering is used in combination Reversed-phase HPLC purifies (Gilson, 30mm x 50mm Gemini column, NH4OH modifying agent), obtain 4- (((3,5- dicyano -4- Ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) methyl) (47mg, 43% produces benzoic acid Rate), it is light yellow solid.LCMS m/z=436 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.86 (d, J= 8.36Hz 2H), 7.43 (d, J=8.11Hz, 2H), 4.55 (s, 2H), 3.74-3.92 (m, 4H), 2.78 (q, J=7.44Hz, 2H), 2.56-2.63 (m, 2H), 2.44-2.49 (m, 2H), 2.21 (s, 3H), 1.86-1.96 (m, 2H), 1.22 (t, J= 7.60Hz, 3H), (carboxylic protons do not observe).
Embodiment 74
2- (dimethylamino) -4- ethyl -6- (((6- oxo -1,6- dihydropyridine -3- base) methyl) sulfenyl) pyridine - 3,5- dimethoxy nitrile
At 0 DEG C, by 48% hydrobromic acid (3mL, 26.5mmol) add to 5- (hydroxymethyl) pyridine -2 (1H) -one (400mg, 3.20mmol), it is then heated 16 hours at 110 DEG C.The mixture is concentrated, crude black liquor (400mg) is obtained.To 2- Chloro- 6- (dimethylamino) -4- ethylpyridine -3,5- dimethoxy nitrile (describe synthesis in embodiment 3, step 3,200mg, Thioacetic acid potassium (188mg, 1.646mmol) 0.823mmol) is added simultaneously in the solution in n,N-Dimethylformamide (10mL) The reaction mixture is stirred at room temperature 2 hours.After 2 hours, which is cooled to 0 DEG C, potassium carbonate is then added Simultaneously the mixture is stirred at room temperature 1 hour for (228mg, 1.646mmol) and crude black liquor (400mg).By the reactant Matter is diluted with ethyl acetate (100mL) and is washed with HCL aqueous solution (1N, 2x 100mL).Organic layer is passed through into anhydrous Na2SO4It is dry It is dry, it filters and evaporates the filter vacuum, obtain crude compound.The thick matter compound is passed through into silica gel chromatography (100-200 mesh is eluted with the DCM solution of 3-4% methanol), obtain 2- (dimethylamino) -4- ethyl -6- (((oxo -1 6-, 6- dihydropyridine -3- base) methyl) sulfenyl) pyridine -3,5- dimethoxy nitrile (115mg, 41%) is brown solid.LCMS m/z= 340.1[M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 11.5 (s, 1H), 7.4 (dd, J=2.4Hz, J=2.8Hz, 1H), 7.4 (s, 1H), 6.2 (d, J=9.2Hz, 1H), 4.2 (s, 2H), 3.2-3.4 (2s, 6H), 2.7 (q, J=7.6Hz, 2H), 1.2 (t, J=7.6Hz, 3H).
Embodiment 75
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) thiazol-2-yl) acetamide
Step 1:N- (4- (chloromethyl) thiazol-2-yl) acetamide
By solution of 4- (chloromethyl) thiazole -2- amine hydrochlorate (249mg, 1.345mmol) in tetrahydrofuran (3mL) It is cooling in ice bath, chloroacetic chloride (0.115mL, 1.614mmol) then is added.Be then slowly added into triethylamine (0.375mL, 2.69mmol) the solution in tetrahydrofuran (3mL).The reaction is stirred 30 minutes in ice bath, then uses the reaction EtOAc (10mL) dilution, is then washed with water.It separates organic layer and extracts water layer with EtOAc (2x 10mL).This is organic Object merges and is washed with saturated sodium-chloride water solution, uses MgSO4It is dried, filtered and concentrated to obtain white solid.Then this is consolidated Body DCM and hexanes trituration, are then isolated by filtration, obtain N- (4- (chloromethyl) thiazol-2-yl) acetamide (175mg, 0.918mmol, 68% yield), it is white solid.LCMS m/z=190.9 [M+H]+。
Step 2:N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyrrole Pyridine -2- base) sulfenyl) methyl) thiazol-2-yl) acetamide
To 4- ethyl -2- sulfydryl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -3,5- dimethoxy nitrile (in reality Example 69 is applied, synthesis, 52mg, 0.138mmol are described in step 1) N- (4- (chlorine is added in n,N-Dimethylformamide (2mL) Methyl) thiazol-2-yl) acetamide (26.3mg, 0.138mmol) and triethylamine (0.038mL, 0.276mmol).Then this is anti- It should be heated 0.5 hour at 50 DEG C.The reaction is cooled to room temperature, water (10mL) then is added.Then by mixture EtOAc (3x 10mL) extraction.The organic matter is merged, is washed with saturated sodium-chloride water solution, MgSO is used4It is dry, it then filters and subtracts Pressure concentration, then 2 × 10g Biotage Ultra column of loading to the double-deck landfill, is adjusted with hexane, then in 100% hexane Then lower operation 2 minutes runs 2 minutes at 100%DCM, then runs 28 points with the DCM solution of the MeOH of 0-10% gradient Clock obtains required product fraction.Fraction containing required product is merged, is then concentrated under reduced pressure, obtains N- (4- (((3,5- bis- Cyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) methyl) thiazol-2-yl) second Amide (19mg, 0.042mmol, 30% yield), is white solid.LCMS m/z=456.4 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 12.16 (s, 1H), 7.03 (s, 1H), 4.47 (s, 2H), 3.83-3.92 (m, 4H), 2.78 (q, J=7.52Hz, 2H), 2.60 (br.s., 2H), 2.46 (br.s., 2H), 2.22 (s, 3H), 2.12 (s, 3H), 1.93 (br.s., 2H), 1.22 (t, J=7.60Hz, 3H).
Embodiment 76
4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) methyl) benzsulfamide
The solution of 4- (bromomethyl) benzsulfamide is prepared by following steps.By 4- methyl benzenesulfonamide (0.5g, It 2.92mmol) is dissolved in chloroform (10mL) and N- bromine succinimide (0.546g, 3.07mmol) and benzoyl peroxide is added (0.035g, 0.146mmol) and the reaction is heated overnight at 63 DEG C.By the succinimide in crystallizing at room temperature, 4- (bromine is obtained Methyl) benzsulfamide crude solution.By 4- ethyl -2- sulfydryl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine - 3,5- dimethoxy nitriles (synthesis, 180mg, 0.597mmol are described in embodiment 69, step 1) are dissolved in chloroform and diisopropyl are added The chloroformic solution (about 1 equivalent of total mistake) of 4- (bromomethyl) benzsulfamide is then added portionwise in base ethamine (209 μ l, 1.194mmol) Until all starting mercaptan disappears in LCMS.After being stirred at room temperature 1 hour, which is evaporated and the thick material is remaining Object is dissolved in ethyl acetate, is washed with water and dries.The ethyl acetate is removed in vacuum and by raw product loading to 12g silicagel column And with silica gel chromatography (with the hexane solution of 25-100% ethyl acetate, then 10-70% (the acetic acid second containing 26% ethyl alcohol The ethyl acetate solution of ester and 0.1% ammonium hydroxide), obtain 60mg87% pure material.This 87% pure material is dissolved in 1mL In DMSO and with Reverse phase chromatography (aqueous solution of 10-90% acetonitrile, contain 0.1%TFA), 4- (((3,5- dicyanos-are obtained 4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) methyl) benzsulfamide (25mg, 0.053mmol, 8.9% yield).LCMS m/z=472.4 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.78 (d, J =8.36Hz, 2H), 7.60 (s, 2H), 7.36 (s, 2H), 4.58 (s, 2H), 3.77-3.89 (m, 4H), 2.72-2.83 (m, 2H), 2.57-2.65 (m, 2H), 2.41-2.48 (m, 2H), 2.22 (s, 3H), 1.84-1.95 (m, 2H), 1.22 (s, 3H).
Embodiment 77
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) benzyl) acetamide
To 2- ((4- (amino methyl) benzyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) Pyridine -3,5- dimethoxy nitrile dihydrochloride (synthesis, 131mg, 0.265mmol are described in embodiment 71) and triethylamine Acetic anhydride (0.025mL, 0.265mmol) is added in room temperature in the solution of (0.111mL, 0.796mmol) in methylene chloride (1mL) Solution in methylene chloride (0.5mL).After being stirred at room temperature 2 hours, which is concentrated, is obtained the thick production Object.Raw product reversed-phase HPLC is purified into (Gilson, 30mm x 50mm Gemini column, NH4OH modifying agent), obtain N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) methyl) Benzyl) acetamide (47mg, 38% yield) is white solid.LCMS m/z=463 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.34 (t, J=5.70Hz, 1H), 7.34 (d, J=8.11Hz, 2H), 7.21 (d, J=8.36Hz, 2H), 4.47 (s, 2H), 4.21 (d, J=5.83Hz, 2H), 3.82-3.94 (m, 4H), 2.78 (q, J=7.60Hz, 2H), 2.61- 2.68 (m, 2H), 2.45-2.49 (m, J=5.60Hz, 2H), 2.24 (s, 3H), 1.89-1.97 (m, 2H), 1.86 (s, 3H), 1.22 (t, J=7.48Hz, 3H).
Embodiment 78
(2- ((4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) methyl) benzyl) amino) -2- oxoethyl) t-butyl carbamate
It is molten in n,N-Dimethylformamide (1.3mL) to Boc- glycine (47.2mg, 0.270mmol) in room temperature HATU (102mg, 0.270mmol) is added in liquid.Then the reaction mixture is stirred at room temperature 15 minutes, 2- ((4- is added at this time (amino methyl) benzyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -3,5- dimethoxy nitrile two Hydrochloride (synthesis, 133mg, 0.270mmol are described in embodiment 71) and triethylamine (0.038mL, 0.270mmol).? After being stirred overnight at room temperature, which is filtered and purifies (Gilson, 30mm x 50mm Gemini column, NH with reversed-phase HPLC4OH Modifying agent), the required product purified.Then separated material is dissolved in ethyl acetate and be washed with water.Then will have Machine layer is dried and concentrated with magnesium sulfate, obtains (2- ((4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- diazacyclos Heptane -1- base) pyridine -2- base) sulfenyl) methyl) benzyl) amino) -2- oxoethyl) t-butyl carbamate (129mg, It 83%), is light brown colloid.LCMS m/z=578 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.28 (t, J= 5.83Hz, 1H), 7.33 (d, J=8.36Hz, 2H), 7.21 (d, J=7.86Hz, 2H), 7.01 (t, J=6.08Hz, 1H), (4.47 s, 2H), 4.25 (d, J=5.83Hz, 2H), 3.83-3.95 (m, 4H), 3.55 (d, J=6.08Hz, 2H), 2.78 (q, J =7.60Hz, 2H), 2.62-2.70 (m, 2H), 2.24 (s, 3H), 1.88-1.98 (m, 2H), 1.39 (s, 9H), 1.22 (t, J= 7.60Hz, 3H).2H is covered by DMSO.
Embodiment 79
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) benzyl) methylsulfonamides
At 25 DEG C, by 4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyrrole Pyridine -2- base) sulfenyl) methyl) the benzylcarbamate tert-butyl ester (describe synthesis in 69 step 2 of embodiment, 100mg, 0.192mmol) it is dissolved in methylene chloride (2mL).It is added trifluoroacetic acid (1.480mL, 19.21mmol) and reaction stirring 1 is small When.The mixture is concentrated, the residue is then dissolved in methylene chloride, is washed with saturated sodium bicarbonate aqueous solution, is then done It is dry, concentration.In room temperature, which is dissolved in DCM and DIEA (0.067mL, 0.384mmol) is added, methane sulphur is then added dropwise Solution of the acyl chlorides (0.015mL, 0.192mmol) in 1mL DCM.After 15 minutes, the solvent and DIEA are evaporated.By the remnants Object is dissolved in DCM, is washed with sodium bicarbonate aqueous solution, is then washed with water and the organic matter is dried and concentrated.Pass through silica gel color The spectrum purifying residue (being eluted with the ethyl acetate of 10-100% (26% ethyl alcohol contains ammonium hydroxide 1% in ethyl acetate)), Obtain N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) Methyl) benzyl) methylsulfonamides (40mg).LCMS m/z=499.2 [M+H]+。1H NMR (400MHz, DMSO-d6)δppm 7.55 (t, J=6.46Hz, 1H), 7.36-7.41 (m, 2H), 7.30-7.34 (m, 2H), 4.49 (s, 2H), 4.13-4.15 (d, J =6.34Hz, 2H), 3.8-3.98 (m, 4H), 2.85 (s, 3H), 2.75-2.8 (m, 2H), 2.64 (d, J=4.56Hz, 2H), 2.45-2.5 (m, 2H), 2.24 (s, 3H), 1.84-1.99 (m, 2H), 1.22 (t, J=7.60Hz, 3H).
Embodiment 80
2- amino-N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyrrole Pyridine -2- base) sulfenyl) methyl) benzyl) acetamide
By (2- ((4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine - 2- yl) sulfenyl) methyl) benzyl) amino) -2- oxoethyl) t-butyl carbamate (describes in embodiment 69, step 2 Synthesis, 105mg, 0.182mmol) to be stirred at room temperature 2 small for the suspension in the dioxane (4M, 2mL, 8.0mmol) of HCl When.The reaction mixture is concentrated.Resulting materials are suspended in methanol and are handled with isopropylamine.By the mixture reversed-phase HPLC Purify (Gilson, 30mm x 50mm Gemini column, NH4OH modifying agent), obtain 2- amino-N- (4- (((3,5- dicyanos- 4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) methyl) benzyl) acetamide (39mg, It 45%) is, sticky pale orange oil.LCMS m/z=478 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.29 (s, 1H), 7.34 (d, J=8.11Hz, 2H), 7.23 (d, J=8.36Hz, 2H), 4.47 (s, 2H), 4.27 (d, J=6.08Hz, 2H), 3.82-3.95 (m, 4H), 3.12 (s, 2H), 2.78 (q, J=7.52Hz, 2H), 2.60-2.69 (m, 2H), 2.24 (s, 3H), 1.88-1.97 (m, 2H), 1.80 (br.s., 2H), 1.22 (t, J=7.60Hz, 3H), (2H is covered by DMSO).
Embodiment 81
2- (4- amino piperidine -1- base) -6- (benzyl sulfenyl) -4- ethylpyridine -3,5- dimethoxy nitrile
Step 1:(1- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) piperidin-4-yl) t-butyl carbamate
At 0 DEG C, to chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (synthesis is described in embodiment 3, step 2, 1g, 4.19mmol) in tetrahydrofuran (15mL) in agitating solution be added piperidin-4-yl t-butyl carbamate (0.839g, 4.19mmol), triethylamine (1.168mL, 8.38mmol) then is added.The mixture is stirred at room temperature 16 hours.This is anti- It answers mixture to be concentrated in vacuo, obtained crude residue is diluted with water (40mL) and is extracted with ethyl acetate (2x 100mL). By combined organic layer anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure the filtrate, obtain (1- (chloro- 3, the 5- bis- of 6- Cyano -4- ethylpyridine -2- base) piperidin-4-yl) t-butyl carbamate (1g, 60.1%) is pale solid.LCMS M/z=390.3 [M+H]+。
Step 2:(1- (6- (benzyl sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl) carbamic acid The tert-butyl ester
At 0 DEG C, to (1- (chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-) piperidin-4-yl) t-butyl carbamate (700mg, 1.763mmol) in n,N-Dimethylformamide (7mL) in agitating solution be added phenyl methyl mercaptan (219mg, 1.763mmol), potassium carbonate (268mg, 1.939mmol) then is added.The reaction mixture is stirred at room temperature 16 hours.It will The reaction mixture is quenched (30mL) with cold water and is extracted with EtOAc (2x 100mL).By combined organic layer Na2SO4It is dry It is dry, it filters and the filter vacuum is concentrated, obtain crude (1- (6- (benzyl sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) piperidin-4-yl) t-butyl carbamate (500mg).LCMS m/z=478.2 [M+H]+(it is pure that 81% is detected as by LCMS Degree).
Step 3:2- (4- amino piperidine -1- base) -6- (benzyl sulfenyl) -4- ethylpyridine -3,5- dimethoxy nitrile
At 0 DEG C, to crude (1- (6- (benzyl sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl) T-butyl carbamate (430mg) be added in the agitating solution in Isosorbide-5-Nitrae-dioxanes (10mL) HCl (dioxane of 4M, 3mL, 12mmol) and be stirred at room temperature 4 hours.The reaction mixture is concentrated in vacuo, by the thick material residue water (30mL) dilutes and is adjusted to pH8 with saturated sodium bicarbonate aqueous solution (50mL), is then extracted with ethyl acetate (2x 50mL). By combined organic layer Na2SO4It dries, filters and filter vacuum is concentrated, obtain crude compound.By the thick matter chemical combination Object obtains 2- (4- amino piperidine -1- by silica gel chromatography (100-200 mesh is eluted with the DCM solution of 4-5% methanol) Base) -6- (benzyl sulfenyl) -4- ethylpyridine -3,5- dimethoxy nitrile (170mg) is brown glue.LCMS m/z=378.4 [M+H ]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.38 (d, J=6.8Hz, 2H), 7.3 (t, J=7.2Hz, 2H), 7.26 (d, J =6.8Hz, 1H), 4.5 (s, 2H), 4.4 (d, J=12.8Hz, 2H), 3.2-3.4 (m, 2H), 2.9-3.0 (m, 1H), 2.7 (q, J =8Hz, 2H), 1.8-1.9 (m, 2H), 1.2-1.4 (m, 2H), 1.2 (t, J=8Hz, 3H).
Embodiment 82
Acetic acid 4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) methyl) benzyl ester
Terephthalyl alcohol (1.0g, 7.24mmol) is dissolved in tetrahydrofuran (20mL), triethylamine is then successively added The solution of (2.018mL, 14.48mmol) and acetic anhydride (0.683mL, 7.24mmol) in 2mL tetrahydrofuran.The reaction is stirred It mixes overnight, is then heated 1 hour at 60 DEG C.By the reaction be cooled to 10 DEG C and be added methane sulfonyl chloride (0.564mL, 7.24mmol), while triethylamine (2.018mL, 14.48mmol) is added.The reaction is warmed to 25 DEG C and stirs 1 hour simultaneously temperature Heat continues 30 minutes to 60 DEG C, obtains the crude solution of acetic acid 4- (((methyl sulphonyl) oxygroup) methyl) benzyl ester.By 4- second Base -2- sulfydryl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -3,5- dimethoxy nitrile is (in embodiment 69, step 1 Describe synthesis, 250mg, 0.829mmol) it is dissolved in tetrahydrofuran (20mL), then by DIEA (0.435mL, 2.488mmol) point The solution (about 1 equivalent in total) that acetic acid 4- (((methyl sulphonyl) oxygroup) methyl) benzyl ester is added is criticized until all starting sulphur Alcohol disappears in LCMS.The reaction is stirred 1 hour and is heated to 60 DEG C and continues 30 minutes.The tetrahydrofuran is evaporated and will be thick Product processed is dissolved in methylene chloride and loading to 12g silicagel column and purifying (is eluted 7 minutes with ethyl acetate, then carry out 0-45% Gradient (ethyl acetate solution of 26% ethyl alcohol, contain 0.1% ammonium hydroxide) ethyl acetate solution).By the product fraction of alcohol Merge, obtains acetic acid 4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) methyl) benzyl ester (180mg, 0.378mmol, 46% yield.LCMS m/z=464.4 [M+H]+。1H NMR (chlorine Imitative-d) δ ppm 7.33-7.42 (m, 4H), 5.12 (s, 2H), 4.43 (s, 2H), 4.18 (br.s., 2H), 3.97 (t, J= 6.2Hz, 2H), 2.77-3.16 (m, 6H), 2.64 (br.s., 3H), 2.26-2.55 (m, 2H), 2.15 (s, 3H), 1.37 (t, J =7.6Hz, 3H).
Embodiment 83
2- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) phenyl-acetamides
In room temperature, to 2- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) Pyridine -2- base) sulfenyl) methyl) phenyl) acetic acid (synthesis, 51mg, 0.113mmol are described in embodiment 72) is in N, N- bis- HATU (43mg, 0.113mmol) is added in solution in methylformamide (0.7mL).Then by the reaction mixture in room temperature The methanol solution of the ammonium hydroxide (7M, 0.05mL, 0.350mmol) of 0.05mL is added in stirring 30 minutes at this time.Then the reaction is mixed It closes object and is warmed to 40 DEG C, stirred 6 hours in the temperature.The reaction mixture is cooling, it is stirred at room temperature overnight.By the mixture It filters and purifies (Gilson, 30mm x 50mm Gemini column, NH with reversed-phase HPLC4OH modifying agent), obtain 2- (4- (((3, 5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) methyl) phenyl) acetyl Amine (35mg, 69% yield), is white solid.LCMS m/z=449 [M+H]+。1H NMR (400MHz, chloroform-d) δ ppm 7.39 (d, J=8.11Hz, 2H), 7.29 (d, J=8.1Hz, 2H), 5.43 (br.s., 2H), 4.44 (s, 2H), 3.99-4.06 (m, 2H), 3.96 (t, J=5.96Hz, 2H), 3.62 (s, 2H), 2.96 (q, J=7.60Hz, 2H), 2.80 (br.s., 2H), 2.66 (br.s., 2H), 2.44 (s, 3H), 2.11 (br.s., 2H), 1.36 (t, J=7.60Hz, 3H).
Embodiment 84
2- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) phenyl)-N- methylacetamide
In room temperature, to 2- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) Pyridine -2- base) sulfenyl) methyl) phenyl) acetic acid (synthesis, 51mg, 0.113mmol are described in embodiment 72) is in N, N- bis- HATU (43mg, 0.113mmol) is added in solution in methylformamide (0.7mL).Then by the reaction mixture in room temperature The solution of methylamine (2M, 0.170mL, 0.340mmol) in ethanol is added in stirring 30 minutes at this time.Then the reaction is mixed Object is warmed to 40 DEG C and stirs 6 hours in the temperature.The reaction mixture is cooled to room temperature and is stirred overnight.By the mixture It filters and purifies (Gilson, 30mm x 50mm Gemini column, NH with reversed-phase HPLC4OH modifying agent), obtain 2- (4- (((3, 5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) methyl) phenyl)-N- Methylacetamide (37mg, 71% yield), is white solid.LCMS m/z=463 [M+H]+。1H NMR (400MHz, DMSO- d6) δ ppm 7.91-7.99 (m, 1H), 7.32 (d, J=8.11Hz, 2H), 7.21 (d, J=8.11Hz, 2H), 4.47 (s, 2H), 3.83-3.95 (m, 4H), 3.36 (s, 2H), 2.78 (q, J=7.60Hz, 2H), 2.62-2.69 (m, 2H), 2.56 (d, J= 4.82Hz, 3H), 2.45-2.49 (m, 2H), 2.23 (s, 3H), 1.87-1.97 (m, 2H), 1.22 (t, J=7.60Hz, 3H).
Embodiment 85
4- ethyl -2- ((4- (hydroxymethyl) benzyl) sulfenyl) -6- (4- methyl-1,4- Diazesuberane -1- base) pyrrole Pyridine -3,5- dimethoxy nitrile
By acetic acid 4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) methyl) benzyl ester (synthesis, 120mg, 0.259mmol are described in embodiment 82) is dissolved in tetrahydrofuran: ethyl alcohol 1:2 mixture in and be added 1mL 1N NaOH and by the reaction stir 3 hours.The pH of the solution is adjusted to 7 with 1N HCl And the solvent is evaporated.The residue is allocated between water and DCM.By the DCM layers dried, filtered with sodium sulphate and by this it is molten Agent evaporation, obtains 4- ethyl -2- ((4- (hydroxymethyl) benzyl) sulfenyl) -6- (4- methyl-1,4- Diazesuberane -1- base) Pyridine -3,5- dimethoxy nitrile (63mg, 0.149mmol, 17.9% yield .LCMS m/z=422.4 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.21-7.41 (m, 4H), 5.19 (t, J=5.58Hz, 1H), 4.45-4.52 (m, 4H), 3.85-3.96 (m, 4H), 3.3-3.35 (m, 2H), 2.75-2.8 (q, J=7.60Hz, 2H), 2.66-2.65 (br.s., 2H), 2.20-2.30 (m, 3H), 1.86-2.01 (m, 2H), 1.22 (t, J=7.60Hz, 3H).
Embodiment 86
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) benzyl) -2- hydroxyl acetamide
In room temperature, to solution of the 2- hydroxyacetic acid (8mg, 0.105mmol) in n,N-Dimethylformamide (0.7mL) Middle addition HATU (39mg, 0.103mmol).Then the reaction mixture is stirred at room temperature 30 minutes, 2- ((4- is added at this time (amino methyl) benzyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -3,5- dimethoxy nitrile two Hydrochloride (describes synthesis, 50mg, 0.101mmol) in embodiment 71, is added triethylamine (0.042mL, 0.304mmol). After 2.5 hours, which is filtered and purifies (Gilson, 30mm x 50mm Gemini column, NH with reversed-phase HPLC4OH changes Property agent), obtain N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) methyl) benzyl) -2- hydroxyl acetamide (24mg, 50% yield) is pale solid.LCMS m/z=479 [M +H]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.28 (t, J=6.21Hz, 1H), 7.33 (d, J=8.11Hz, 2H), 7.23 (d, J=8.11Hz, 2H), 5.52 (t, J=5.83Hz, 1H), 4.47 (s, 2H), 4.27 (d, J=6.34Hz, 2H), 3.78- 3.95 (m, 6H), 2.78 (q, J=7.44Hz, 2H), 2.61-2.68 (m, 2H), 2.44-2.49 (m, 2H), 2.24 (s, 3H), 1.83-1.97 (m, 2H), 1.22 (t, J=7.60Hz, 3H).
Embodiment 87
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) benzyl) propionamide
At 0 DEG C, to 2- ((4- (amino methyl) benzyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- diaza cycloheptyl Alkane -1- base) pyridine -3,5- dimethoxy nitrile dihydrochloride (synthesis, 50mg, 0.101mmol are described in embodiment 71) He Sanyi Amine (42.4 μ l, 0.304mmol) be added in the solution in n,N-Dimethylformamide (1.0mL) propionyl chloride (8.80 μ l, 0.101mmol).Then the reaction mixture is stirred 2 hours at 0 DEG C.After warming to room temperature, simultaneously by reaction mixture filtering Purify (Gilson, 30mm x 50mm Gemini column, NH with reversed-phase HPLC4OH modifying agent), obtain N- (4- (((3,5- dicyan Base -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) methyl) benzyl) propionamide (31mg, 64% yield), is pale solid.LCMS m/z=477 [M+H]+。1H NMR (400MHz, DMSO-d6)δppm 8.26 (t, J=5.96Hz, 1H), 7.34 (d, J=8.11Hz, 2H), 7.20 (d, J=8.11Hz, 2H), 4.47 (s, 2H), 4.22 (d, J=5.83Hz, 2H), 3.80-3.96 (m, 4H), 2.78 (q, J=7.35Hz, 2H), 2.60-2.68 (m, 2H), 2.43-2.49 (m, 2H), 2.24 (s, 3H), 2.13 (q, J=7.60Hz, 2H), 1.86-2.00 (m, 2H), 1.18-1.26 (m, 3H), 1.01 (t, J=7.60Hz, 3H).
Embodiment 88
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) benzyl) isobutyramide
At 0 DEG C, to 2- ((4- (amino methyl) benzyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- diaza cycloheptyl Alkane -1- base) pyridine -3,5- dimethoxy nitrile dihydrochloride (synthesis, 50mg, 0.101mmol are described in embodiment 71) He Sanyi Amine (42.4 μ l, 0.304mmol) be added in the solution in n,N-Dimethylformamide (1.0mL) isobutyryl chloride (10.7 μ l, 0.102mmol).Then the reaction mixture is stirred 2 hours at 0 DEG C.After warming to room temperature, simultaneously by reaction mixture filtering Purify (Gilson, 30mm x 50mm Gemini column, NH with reversed-phase HPLC4OH modifying agent), obtain N- (4- (((3,5- dicyan Base -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) methyl) benzyl) isobutyramide (30mg, 60% yield), is pale solid.LCMS m/z=491 [M+H]+。1H NMR (400MHz, DMSO-d6)δppm 8.25 (t, J=5.96Hz, 1H), 7.30-7.38 (m, J=8.36Hz, 2H), 7.15-7.23 (m, J=8.36Hz, 2H), 4.47 (s, 2H), 4.22 (d, J=5.83Hz, 2H), 3.81-3.98 (m, 4H), 2.78 (q, J=7.60Hz, 2H), 2.67 (br.s., 2H), 2.34-2.46 (m, 1H), 2.25 (s, 3H), 1.83-2.01 (m, 2H), 1.22 (t, J=7.60Hz, 3H), 1.02 (d, J =6.84Hz, 6H).2H covers by DMSO
Embodiment 89
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) benzyl) -3- methylbutyryl amine
At 0 DEG C, to 2- ((4- (amino methyl) benzyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- diaza cycloheptyl Alkane -1- base) pyridine -3,5- dimethoxy nitrile dihydrochloride (synthesis, 50mg, 0.101mmol are described in embodiment 71) He Sanyi 3-Methylbutanoyl chloride (12.4 μ are added in amine (42.4 μ l, 0.304mmol) in the solution in n,N-Dimethylformamide (1.0mL) L, 0.102mmol).Then the reaction mixture is stirred 2 hours at 0 DEG C.After warming to room temperature, which is filtered And purify (Gilson, 30mm x 50mm Gemini column, NH with reversed-phase HPLC4OH modifying agent), obtain N- (4- (((3,5- bis- Cyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) methyl) benzyl) -3- methyl Butyramide (32mg, 63%), is pale solid.LCMS m/z=505 [M+H]+。1H NMR (400MHz, DMSO-d6)δ Ppm 8.29 (t, J=5.96Hz, 1H), 7.31-7.36 (m, J=8.11Hz, 2H), 7.17-7.24 (m, J=8.11Hz, 2H), 4.47 (s, 2H), 4.23 (d, J=6.08Hz, 2H), 3.82-3.95 (m, 4H), 2.78 (q, J=7.60Hz, 2H), 2.61- 2.69 (m, 2H), 2.45-2.49 (m, 2H), 2.24 (s, 3H), 1.98-2.03 (m, 3H), 1.89-1.96 (m, 2H), 1.22 (t, J=7.60Hz, 3H), 0.87 (d, J=6.34Hz, 6H).
Embodiment 90
4- ethyl -2- ((4- (((2- hydroxyethyl) amino) methyl) benzyl) sulfenyl) -6- (4- methyl-1,4- diaza Cycloheptane -1- base) pyridine -3,5- dimethoxy nitrile
At 0 DEG C, to 2- ((4- (amino methyl) benzyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- diaza cycloheptyl Alkane -1- base) pyridine -3,5- dimethoxy nitrile dihydrochloride (synthesis, 50mg, 0.101mmol are described in embodiment 71) He Sanyi Solution of the amine (16.57 μ l, 0.119mmol) in n,N-Dimethylformamide (0.4mL) be added ethylene bromohyrin (8.5 μ l, 0.120mmol) the solution in N,N-dimethylformamide (0.6mL).After 0 DEG C is stirred overnight, then by the reaction 40 DEG C reheat 24 hours.Additional 8.5uL ethylene bromohyrin and 16.6uL triethylamine are added into the reaction mixture and by it 40 DEG C stirring is for the weekend.The reaction mixture is cooled to room temperature, filter and purifies (Gilson, 30mm x 50mm with reversed-phase HPLC Gemini column, NH4OH modifying agent), obtain 4- ethyl -2- ((4- (((2- hydroxyethyl) amino) methyl) benzyl) sulfenyl) -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -3,5- dimethoxy nitrile (6mg, 11% yield) is light brown colloid. LCMS m/z=465 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.33 (d, J=8.11Hz, 2H), 7.28 (d, J= 8.11Hz, 2H), 4.43-4.51 (m, 3H), 3.81-3.95 (m, 4H), 3.67 (s, 2H), 3.45 (q, J=5.66Hz, 2H), 2.78 (q, J=7.60Hz, 2H), 2.63-2.68 (m, 2H), 2.53-2.56 (m, 2H), 2.47 (d, J=5.58Hz, 2H), 2.23 (s, 3H), 2.03 (br.s., 1H), 1.85-1.98 (m, 2H), 1.22 (t, J=7.60Hz, 3H).
Embodiment 91
N- (4- (((3,5- dicyano -6- (4- methyl-1,4- Diazesuberane -1- base) -4- (methylamino) pyrrole Pyridine -2- base) sulfenyl) methyl) benzyl) acetamide
Step 1:2- amino -6- sulfydryl -4- (methylsulfany) pyridine -3,5- dimethoxy nitrile
By 2- (bis- (methylsulfany) methylene) malononitrile (10g, 58.7mmol) and cyano-thioacetamide (7.06g, It 70.5mmol) adds to round-bottomed flask and is dissolved in N,N-dimethylformamide (21mL).By triethylamine (16.37mL, 117mmol) It is added dropwise in room temperature and stirs the mixture 18 hours.The reaction mixture is added into 300mL 3N hydrochloric acid.Gained was precipitated It filters, be washed with water and filter drying with passing through, obtain 2- amino -6- sulfydryl -4- (methylsulfany) pyridine -3,5- dimethoxy nitrile (13.5g, 54.7mmol, 93% yield).LCMS m/z=222.9 [M+H]+。
Step 2:4- (((6- amino -3,5- dicyano -4- (methylsulfany) pyridine -2- base) sulfenyl) methyl) benzyl ammonia Base t-butyl formate
By 2- amino -6- sulfydryl -4- (methylsulfany) pyridine -3,5- dimethoxy nitrile (1g, 4.50mmol) and sodium bicarbonate water Solution (1g, 11.90mmol) adds to round-bottomed flask, is suspended in n,N-Dimethylformamide (30mL).Simultaneously by mixture stirring 4- (bromomethyl) the benzylcarbamate tert-butyl ester (1.5g, 5.00mmol) is added slowly to the mixture.By the solution in room temperature Stirring 1 hour.NaHCO will be saturated3Aqueous solution adds in the mixture and extracts water phase EtOAc (3x).By merging Organic matter is washed with brine, and is dried, filtered and concentrated yellowly oil with magnesium sulfate.By the residue grinding of DCM/ heptane and mistake The sediment is filtered, 4- (((6- amino -3,5- dicyano -4- (methylsulfany) pyridine -2- base) sulfenyl) methyl) benzyl is obtained T-butyl carbamate (1.65g, 3.74mmol, 83% yield).LCMS m/z=442.2 [M+H]+。
Step 3:N- (4- (((6- amino -3,5- dicyano -4- (methylsulfany) pyridine -2- base) sulfenyl) methyl) benzyl Base) acetamide
By 4- (((6- amino -3,5- dicyano -4- (methylsulfany) pyridine -2- base) sulfenyl) methyl) benzylamino first Tert-butyl acrylate (414mg, 0.938mmol) and HCl (12mL, 48.0mmol；The 1,4- dioxane of 4M) add to round-bottomed flask And it is stirred at room temperature 15 minutes.The mixture is concentrated in vacuo, is suspended in EtOAc/ ether and filters out the solid and be used in combination Ether/heptane wash.The sediment is suspended in DCM (10mL) and triethylamine (0.392mL, 2.81mmol) and acetic anhydride is added (0.088mL, 0.938mmol).The mixture is stirred at room temperature 15 minutes, lcms analysis indicates required product.By the suspension Liquid is cooled to 0 DEG C and the sediment is collected by filtration.By sediment ether/heptane wash, N- (4- (((6- is obtained Amino -3,5- dicyano -4- (methylsulfany) pyridine -2- base) sulfenyl) methyl) benzyl) acetamide (402mg) roughage, will It is directly carried out without purification.LCMS m/z=384.2 [M+H]+。
Step 4:N- (4- (((3,5- dicyano -6- (4- methyl-1,4- Diazesuberane -1- base) -4- (methyl ammonia Base) pyridine -2- base) sulfenyl) methyl) benzyl) acetamide
By N- (4- (((6- amino -3,5- dicyano -4- (methylsulfany) pyridine -2- base) sulfenyl) methyl) benzyl) second Amide (290mg；From crude material obtained in the previous step) and copper chloride (II) (200mg, 1.488mmol) add to round-bottomed flask simultaneously It is suspended in acetonitrile (10mL).The mixture is heated to 40 DEG C and continues 5 minutes.By nitrite tert-butyl (0.15mL, It 1.266mmol) is added slowly to the mixture and stirs the mixture 60 minutes at 45 DEG C.It is reacted and is stopped by lcms analysis, Therefore 0.05mL nitrite tert-butyl and 50mg CuCl are added into the mixture of the heating2And every 20 minutes by LCMS after Continuous monitoring.Nitrite tert-butyl (0.05mL) and CuCl is added2(50mg) is until lcms analysis shows that starting material is almost complete It totally disappeared consumption.By the mixture by small silicagel pad/It filters and is washed with EtOAc:EtOH 4:1.The filtrate is used into 1- Methyl-1,4- Diazesuberane (0.235mL, 1.891mmol) and DIPEA (1mL) processing.The solution turned blue, passes through LCMS Monitoring reaction is until chloromethylated intermediate exhausts.The solution is concentrated, the residue is then purified into (0-50- using reversed-phase column chromatography 100%0.1%NH4The acetonitrile solution of OH aqueous solution).Required fraction is merged and is concentrated, residue is obtained.By methylamine (4mL, 51.5mmol；40% H2O solution) it adds to the residue and is stirred 2 hours at 50 DEG C.It is concentrated to get residue, then by it It is purified on C18Aq. column.Use reverse phase Isco chromatographic column (0-40-50-100%0.1%NH4OH aqueous solution/acetonitrile), by institute It needs fraction to merge, is concentrated by nitrogen stream, obtain N- (4- (((3,5- dicyano -6- (4- methyl-1,4- Diazesuberane - 1- yl) -4- (methylamino) pyridine -2- base) sulfenyl) methyl) benzyl) acetamide (24mg, 0.05mmol, 6% yield).LCMS M/z=464.3 [M+H]+。1H NMR (400MHz, CDCl3) δ ppm 8.32 (s, 1H) 7.32 (d, J=8.11Hz, 2H) 7.16- 7.26 (m, 3H) 4.40 (s, 2H) 4.21 (d, J=5.83Hz, 2H) 3.69-3.85 (m, 4H) 3.13 (s, 3H) 2.58-2.66 (m, 2H) 2.42-2.47 (m, 2H) 2.22 (s, 3H) 1.92 (d, J=4.82Hz, 2H) 1.85 (s, 3H).
Embodiment 92
2- (((2- acetyl group -1,2,3,4- tetrahydroisoquinoline -6- base) methyl) sulfenyl) -6- (dimethylamino) -4- second Yl pyridines -3,5- dimethoxy nitrile
- 2 (1H)-t-butyl formate of step 1:6- (hydroxymethyl) -3,4- dihydro-isoquinoline
Under environment temperature, argon atmospher, in closed flask, by borine-tetrahydrofuran compound in tetrahydrofuran Solution (1.0M, 15.87mL, 15.87mmol) is added dropwise to 2- (tertbutyloxycarbonyl) -1,2,3,4- tetrahydroisoquinoline -6- formic acid (2.0g, 7.21mmol) is in the agitating solution in tetrahydrofuran (50mL).After stirring 3 hours, which is carefully used Water quenching goes out and sodium bicarbonate solution is added.The mixture is extracted with ethyl acetate (x2), slightly object is taken to be washed with salt merging It washs, dry (anhydrous Na2SO4) and evaporation, obtain 6- (hydroxymethyl) -3,4- dihydro-isoquinoline -2 (1H)-t-butyl formate (2.0g).LCMS m/z=207.9 [M+H-isobutene]+。
- 2 (1H)-t-butyl formate of step 2:6- (bromomethyl) -3,4- dihydro-isoquinoline
At 0 DEG C, by 6- (hydroxymethyl) -3,4- dihydro-isoquinoline -2 (1H)-t-butyl formate (2.0g, 7.59mmol) Solution and N- ethyl-N-iospropyl propyl- 2- amine (2.045mL, 11.39mmol) dibromo triphenylphosphine in chloroform (25mL) (4.81g, 11.39mmol) processing, stirs 1 hour, then evaporates.Flash chromatography (heptan of silica gel 40g, 0-30% methylene chloride Alkane solution), obtaining 6- (bromomethyl) -3,4- dihydro-isoquinoline -2 (1H)-t-butyl formate, (1.33g, 4.08mmol, 54% are produced Rate).LCMS m/z=270.0,272.0 [M+H-isobutene]+。
Step 3:2- (dimethylamino) -4- ethyl -6- mercaptopyridine -3,5- dimethoxy nitrile
At -20 DEG C, to dimethylamine hydrochloride (9.02g, 111mmol) and 2, chloro- 4- ethylpyridine -3, the 5- diformazan of 6- bis- Nitrile (describing synthesis, 25g, 111mmol in 3 step 2 of embodiment) is slowly added dropwise three in the suspension in ethyl alcohol (100mL) Solution of the ethamine (30.8mL, 221mmol) in ethyl alcohol (20mL).Then the reaction mixture is stirred 15 minutes at -20 DEG C, It is then heated to 0 DEG C.Then the reaction mixture is stirred at 0 DEG C, is gradually warmed to room temperature 1 hour.Then mixed to the reaction It closes and triethylamine (15.41mL, 111mmol) and thioacetic acid potassium (20.21g, 177mmol) is added in object.Then this is heterogeneous Reaction mixture is warmed to 40 DEG C, stirs in the temperature and monitors process with LCMS simultaneously.After 4 hours, LCMS is indicated in remaining Mesosome is seldom and there are required products.Therefore the crude reaction is concentrated, is then allocated between 1NHCl aqueous solution and chloroform. It is dry with sodium sulphate then by organic layer salt water, water washing, it then filters to remove the desiccant.The solution vacuum is dense Then contracting is dried residue triturated under ether and in a vacuum drying oven, obtains 2- (dimethylamino) -4- ethyl -6- Mercaptopyridine -3,5- dimethoxy nitrile (22.2g, 96mmol, 86% yield) is brown solid.LCMS m/z=233.1 [M+H]+。
Step 4:6- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl) -3,4- Dihydro-isoquinoline -2 (1H)-t-butyl formate
By 6- (bromomethyl) -3,4- dihydro-isoquinoline -2 (1H)-t-butyl formate (256mg, 0.785mmol) in chloroform Solution 2- (dimethylamino) -4- in (20mL) and N- ethyl-N-iospropyl propyl- 2- amine (0.211mL, 1.177mmol) Ethyl -6- mercaptopyridine -3,5- dimethoxy nitrile (182mg, 0.785mmol) processing, is then stirred 1 hour.Due to the sulfydryl pyrrole Pyridine is impure, therefore more will partially be added to push the reaction to complete.The mixture is subjected to silica gel chromatograph and flash chromatography (n-heptane solution of silica gel 40g, 0-30% ethyl acetate) obtains 6- (((3,5- dicyano -6- (dimethylamino) -4- ethyls Pyridine -2- base) sulfenyl) methyl) (290mg, 0.607mmol, 77% are produced -3,4- dihydro-isoquinoline -2 (1H)-t-butyl formate Rate).LCMS m/z=378.2 [M+H-Boc]+。
Step 5:2- (dimethylamino) -4- ethyl -6- (((1,2,3,4- tetrahydroisoquinoline -6- base) methyl) sulfenyl) Pyridine -3,5- dimethoxy nitrile
By 6- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl) -3,4- dihydro Isoquinolin -2 (1H)-solution trifluoroacetic acid of the t-butyl formate (290mg, 0.607mmol) in chloroform (10mL) (1.00mL, 12.98mmol) is handled and is stirred 1 hour.The mixture is evaporated and uses chloroform azeotropic twice.The residue is molten In ethyl alcohol and potassium carbonate is added, heats to ensure to remove the trifluoroacetic acid.The mixture is cooling, pass throughFiltering And it evaporates.The residue is dissolved in chloroform and is refiltered to remove any remaining potassium carbonate.The residue is tied again from ether Crystalline substance collects solid, then dry (50 DEG C, high vacuum) obtains 2- (dimethylamino) -4- ethyl-with ether and heptane wash 6- (((1,2,3,4- tetrahydroisoquinoline -6- base) methyl) sulfenyl) pyridine -3,5- dimethoxy nitrile (60mg, 0.159mmol, 26.2% Yield).By mother liquid evaporation, residue (~100mg) is obtained, is used in next step.LCMS m/z=378.2 [M+H]+。
Step 6:2- (((2- acetyl group -1,2,3,4- tetrahydroisoquinoline -6- base) methyl) sulfenyl) -6- (dimethylamino Base) -4- ethylpyridine -3,5- dimethoxy nitrile
By 2- (dimethylamino) -4- ethyl -6- (((1,2,3,4- tetrahydroisoquinoline -6- base) methyl) sulfenyl) pyridine - Solution and potassium carbonate (183mg, 1.324mmol) of 3, the 5- dimethoxy nitriles (100mg, 0.265mmol) in acetone (10mL) use second Acyl chlorides (0.023mL, 0.318mmol) is handled and is stirred 1 hour.The mixture is evaporated, the pulp in chloroform by the residue And pass throughIt filters and uses chloroform.The solution is evaporated into agglutination, it is stirred in ether, it is solid to collect gained Then dry (50 DEG C, high vacuum) body obtains 2- (((2- acetyl group -1,2,3,4- Tetrahydroisoquinoli-s with ether and heptane wash Quinoline -6- base) methyl) sulfenyl) (60mg, 0.143mmol, 54% are produced -6- (dimethylamino) -4- ethylpyridine -3,5- dimethoxy nitrile Rate).LCMS m/z=420.3 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.20-7.27 (m, 2H), 7.11-7.17 (m, 1H), 4.61 (s, 1H), 4.56 (s, 1H), 4.47 (s, 2H), 3.63 (t, J=6.0Hz, 2H), 3.35 (s, 6H), 2.84 (t, J=5.8Hz, 1H), 2.69-2.80 (m, 3H), 2.07 (s, 3H), 1.21 (t, J=7.6Hz, 3H).
Embodiment 93
2- ((4- cyanobenzyls) sulfenyl) -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -3, 5- dimethoxy nitrile
By 4- ethyl -2- sulfydryl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -3,5- dimethoxy nitrile (in reality Apply example 69, synthesis, 200mg, 0.664mmol described in step 1) be dissolved in it is in n,N-Dimethylformamide (3mL) and this is molten Liquid is cooled to 0 DEG C.Et is added34- (the bromine being dissolved in n,N-Dimethylformamide is then added dropwise in N (0.185mL, 1.327mmol) Methyl) benzonitrile (104mg, 0.531mmol).This is swift in response, and then carries out LCMS until starting mercaptan disappears.By the N, N- bis- Methylformamide evaporates and the thick material residue is dissolved in ethyl acetate, is washed with water and dry with sodium sulphate.This is crude Materials'use 12g silica gel column purification (with 0-47% gradient (ethyl acetate solution of 26% ethyl alcohol contains 0.1% hydroxide Ammonium) ethyl acetate solution elution), obtain 2- ((4- cyanobenzyls) sulfenyl) -4- ethyl -6- (4- methyl-1,4- diaza cycloheptyl Alkane -1- base) pyridine -3,5- dimethoxy nitrile (250mg, 0.600mmol, 90% yield).LCMS m/z=417.2 [M+H]+。1H NMR (methanol-d4) δ ppm 7.72-7.77 (m, 2H), 7.61-7.67 (m, 2H), 4.62 (s, 2H), 4.03-4.13 (m, 2H), 3.99 (t, J=6.2Hz, 2H), 3.28 (m, 4H), 2.96 (q, J=7.6Hz, 2H), 2.81 (s, 3H), 2.22-2.33 (m, 2H), 1.34 (t, J=7.6Hz, 3H).
Embodiment 94
2- amino-N- (1- (6- (benzyl sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl) acetyl Amine, trifluoroacetate
Step 1:4- (2- ((tertbutyloxycarbonyl) amino) acetylamino) piperidines -1- benzyl formate
To 2- ((tertbutyloxycarbonyl) amino) acetic acid (300mg, 1.71mmol) in the solution in tetrahydrofuran (10mL) It is added CDI (417mg, 2.57mmol).The mixture is stirred 2 hours at 60 DEG C, then cools to room temperature, 4- ammonia is then added The mixture is simultaneously stirred overnight by phenylpiperidines -1- benzyl formate (401mg, 1.71mmol).Under reduced pressure by the reaction mixture Then the residue is diluted with ethyl acetate (20mL), is washed with water (3x 20mL), then depressurizing organic layer by concentration Lower concentration obtains crude 4- (2- ((tertbutyloxycarbonyl) amino) acetylamino) piperidines -1- benzyl formate (500mg), is White solid.LCMS m/z=414.1 [M+Na]+。
Step 2:(2- oxo -2- (piperidin-4-yl amino) ethyl) t-butyl carbamate
To 4- (2- ((tertbutyloxycarbonyl) amino) acetylamino) piperidines -1- benzyl formate (500mg) at methanol (20mL) In solution in be added palladium/carbon (15wt%, 40.8mg, 0.383mmol).The mixture is stirred under room temperature nitrogen atmosphere Then night filters and is concentrated under reduced pressure, obtain crude (2- oxo -2- (piperidin-4-yl amino) ethyl) t-butyl carbamate (300mg) is white solid.LCMS m/z=258.1 [M+H]+。
Step 3:(2- ((1- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) piperidin-4-yl) amino) -2- oxo Ethyl) t-butyl carbamate
To chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in embodiment 3, step 2,264mg, (2- oxo -2- (piperidin-4-yl amino) ethyl) carbamic acid 1.16mmol) is added in the solution in methylene chloride (5mL) The tert-butyl ester (300mg, 1.16mmol) and triethylamine (0.162mL, 1.16mmol).The mixture is stirred at room temperature 30 minutes, Then it is washed with salt water (2x 50mL).Organic layer is concentrated under reduced pressure, crude (2- ((1- (chloro- 3, the 5- dicyan of 6- is obtained Base -4- ethylpyridine -2- base) piperidin-4-yl) amino) -2- oxoethyl) t-butyl carbamate (500mg) is yellow Solid.LCMS m/z=469.0 [M+Na]+。
Step 4:(2- ((1- (6- (benzyl sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl) ammonia Base) -2- oxoethyl) t-butyl carbamate
To (2- ((1- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) piperidin-4-yl) amino) -2- oxo second Base) phenyl first is added in t-butyl carbamate (500mg, 1.1mmol) in the solution in n,N-Dimethylformamide (20mL) Mercaptan (139mg, 1.1mmol) and cesium carbonate (729mg, 2.2mmol).The mixture is stirred at room temperature overnight, is then depressurized Concentration.The residue is diluted with ethyl acetate (50mL) and is washed with salt water (3x 50mL).Organic layer is dense under reduced pressure Contracting, obtains crude (2- ((1- (6- (benzyl sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl) amino) - 2- oxoethyl) t-butyl carbamate (500mg) is red solid.LCMS m/z=557.1 [M+Na]+。
Step 5:2- amino-N- (1- (6- (benzyl sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidines -4- Base) acetamide, trifluoroacetate
To crude (2- ((1- (6- (benzyl sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl) ammonia Base) -2- oxoethyl) trifluoroacetic acid is added in the solution in methylene chloride (20mL) in t-butyl carbamate (500mg) (4mL, 51.9mmol).The mixture is stirred overnight and is concentrated under reduced pressure, raw product is obtained, by its with preparative-HPLC into The purifying of one step, obtains 2- amino-N- (1- (6- (benzyl sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl) Acetamide, trifluoroacetate (120mg, 0.219mmol), is white solid.LCMS m/z=435.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.42 (d, J=7.4Hz, 1H), 8.02 (s, 3H), 7.42 (d, J=7.1Hz, 2H), 7.32 (dt, J=25.0,7.1Hz, 3H), 4.51 (s, 2H), 4.39 (d, J=13.5Hz, 2H), 3.99 (m, 1H), 3.55 (s, 2H), 3.41 (t, J=11.3Hz, 2H), 2.78 (q, J=7.5Hz, 2H), 1.93 (d, J=10.4Hz, 2H), 1.49 (dd, J= 20.6,10.2Hz, 2H), 1.22 (t, J=7.6Hz, 3H).
Embodiment 95
2- amino-N- (1- (6- (benzyl sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl) -2- first Base propionamide, formates
Step 1:3- ((tertbutyloxycarbonyl) amino) -3 Methylbutanoic acid
3- amino -3 Methylbutanoic acid (2.06g, 17.5mmol) is dissolved in water (40mL) and (Boc)2O (4.08mL, Water (20mL) solution of sodium hydroxide (0.703g, 17.5mmol) 17.5mmol) and at 0 DEG C is added.By the mixture in room temperature Stirring 12 hours.By solution saturation NH4Cl solution (200mL) and ethyl acetate (60mL) dilution, organic phase is separated, is used Water (30mL) and salt water (30mL) washing, drying are simultaneously concentrated under reduced pressure, and obtain product 3- ((tertbutyloxycarbonyl) amino) -3- methyl fourth Sour (2.1g, 9.67mmol, 55% yield), is white solid.1H NMR (400MHz, DMSO-d6) δ ppm 12.17 (s, 1H), 7.03 (s, 1H), 1.37 (s, 9H), 1.30 (s, 6H).
Step 2:4- (2- ((tertbutyloxycarbonyl) amino) -2- methyl propanamide base) piperidines -1- benzyl formate
To 2- ((tertbutyloxycarbonyl) amino) -2 Methylpropionic acid (300mg, 1.47mmol) in n,N-Dimethylformamide 4- amino piperidine -1- benzyl formate (346mg, 1.47mmol), HATU (842mg, 2.21mmol) are added in solution in (5mL) With DIPEA (0.773mL, 4.43mmol).Gained mixture is stirred overnight at 80 DEG C, is then concentrated under reduced pressure to give the thick production Object.Raw product is added into silicagel column and is eluted with methylene chloride/methanol, 4- (2- ((tertbutyloxycarbonyl) amino) -2- first is obtained Base propionamido-) piperidines -1- benzyl formate (500mg, 1.192mmol, 81% yield) is white solid.LCMS m/z= 442.1[M+Na]+。
Step 3:(2- methyl-1-oxo-1- (piperidin-4-yl amino) propyl- 2- yl) t-butyl carbamate
To 4- (2- ((tertbutyloxycarbonyl) amino) -2- methyl propanamide base) piperidines -1- benzyl formate (500mg, Palladium/carbon (15wt%, 38.1mg, 0.358mmol) 1.192mmol) is added in the solution in methanol (20mL).By the mixture It is stirred overnight under room temperature nitrogen atmosphere, then filters and be concentrated under reduced pressure, obtain (2- methyl-1-oxo-1- (piperidin-4-yl ammonia Base) propyl- 2- yl) t-butyl carbamate (340mg, 1.19mmol, 100% yield) is gray solid.LCMS m/z= 286.1[M+H]+。
Step 4:(1- ((1- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) piperidin-4-yl) amino) -2- first Base -1- oxo propyl- 2- yl) t-butyl carbamate
To chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in embodiment 3, step 2,238mg, (2- methyl-1-oxo-1- (piperidin-4-yl amino) propyl- 2- 1.05mmol) is added in the solution in methylene chloride (20mL) Base) t-butyl carbamate (300mg, 1.05mmol) and triethylamine (0.207mL, 1.48mmol), by the mixture in room temperature Stirring 30 minutes, is then washed with salt water (2x 50mL).Then organic layer is concentrated under reduced pressure, obtains crude (1- ((1- (the chloro- 3,5- dicyano-4- ethylpyridine-2- base of 6-) piperidin-4-yl) amino)-2- methyl-1-oxo propyl- 2- yl) amino first Tert-butyl acrylate (500mg), is yellow solid.LCMS m/z=497.1 [M+Na]+。
Step 5:2- amino-N- (1- (6- (benzyl sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidines -4- Base) -2- methyl propanamide, formates
To (1- ((1- (the chloro- 3,5- dicyano-4- ethylpyridine-2- base of 6-) piperidin-4-yl) amino)-2- methyl-1- Oxo propyl- 2- yl) phenyl first is added in t-butyl carbamate (500mg) in the solution in N,N-dimethylformamide (20mL) Mercaptan (131mg, 1.1mmol) and cesium carbonate (686mg, 2.1mmol).The mixture is stirred at room temperature overnight, is then depressurized Concentration.The mixture is diluted with ethyl acetate (50mL) and is washed with salt water (3x 50mL).Organic layer is dense under reduced pressure Contracting, obtains the reddish oil of 500mg.The oil is dissolved in methylene chloride (20mL), is added trifluoroacetic acid (4mL, 51.9mmol).It will The mixture is stirred overnight, and is then concentrated under reduced pressure, and raw product is obtained, it is purified with preparative-HPLC, obtains 2- amino- N- (1- (6- (benzyl sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl) -2- methyl propanamide, formates (120mg, 0.23mmol).LCMS m/z=463.1 [M+H]+。1H NMR (400MHz, DMSO) δ ppm 8.16 (s, 3H), 8.08 (d, J=7.6Hz, 1H), 7.42 (d, J=7.3Hz, 2H), 7.38-7.24 (m, 3H), 4.51 (s, 3H), 4.47 (s, 1H), (4.00 d, J=6.8Hz, 1H), 3.32 (t, J=12.0Hz, 2H), 2.78 (q, J=7.5Hz, 2H), 1.88 (d, J= 10.3Hz, 2H), 1.54 (dd, J=21.1,11.4Hz, 2H), 1.45 (s, 6H), 1.22 (t, J=7.6Hz, 3H).2H is not observed It arrives.
Embodiment 96
3- amino-N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyrrole Pyridine -2- base) sulfenyl) methyl) benzyl) propionamide
Step 1:(3- ((4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyrrole Pyridine -2- base) sulfenyl) methyl) benzyl) amino) -3- oxopropyl) t-butyl carbamate
In room temperature, to 3- ((tertbutyloxycarbonyl) amino) propionic acid (32mg, 0.169mmol) in n,N-Dimethylformamide HATU (102mg, 0.270mmol) is added in solution in (1.3mL).Then the reaction mixture is stirred at room temperature 30 points 2- ((4- (amino methyl) benzyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) is added in clock at this time Pyridine -3,5- dimethoxy nitrile dihydrochloride (synthesis, 133mg, 0.270mmol are described in embodiment 71) and triethylamine (0.038mL, 0.270mmol).Then the reaction mixture is stirred at room temperature overnight.The mixture is filtered and uses reverse phase HPLC purifies (Gilson, 30mm x 50mm Gemini column, NH4OH modifying agent), obtains (3- ((4- (((3,5- dicyano -4- Ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) methyl) benzyl) amino) -3- oxo third Base) t-butyl carbamate (60mg, 67%) is greenish orange coloring agent.LCMS m/z=592 [M+H]+。
Step 2:3- amino-N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- Base) pyridine -2- base) sulfenyl) methyl) benzyl) propionamide
By (3- ((4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine - 2- yl) sulfenyl) methyl) benzyl) amino) -3- oxopropyl) t-butyl carbamate (34mg, 0.057mmol) HCl (4M, 1.5mL, 6.0mmol) dioxane in suspension be stirred at room temperature 2 hours.Then the reaction mixture is concentrated.It will Resulting materials are suspended in MeOH and free-basing (free based) with isopropylamine.The mixture is purified with reversed-phase HPLC (Gilson, 30mm x 50mm Gemini column, NH4OH modifying agent), obtain 3- amino-N- (4- (((3,5- dicyano -4- second Base -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) methyl) benzyl) propionamide (20mg, It 70.8%), is greenish orange coloring agent.LCMS m/z=492 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.40 (t, J= 5.83Hz 1H), 7.30-7.38 (m, J=8.11Hz, 2H), 7.17-7.25 (m, J=8.11Hz, 2H), 4.47 (s, 2H), 4.24 (d, J=6.08Hz, 2H), 3.83-3.94 (m, 4H), 2.71-2.83 (m, 4H), 2.61-2.69 (m, 2H), 2.48 (d, J =5.83Hz, 2H), 2.24 (s, 3H), 2.21 (t, J=6.59Hz, 2H), 1.86-1.99 (m, 2H), 1.50 (br.s., 2H), 1.22 (t, J=7.60Hz, 3H).
Embodiment 97
(S) -2- amino-N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- Base) pyridine -2- base) sulfenyl) methyl) benzyl) propionamide
Step 1:(S)-(1- ((4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- Base) pyridine -2- base) sulfenyl) methyl) benzyl) amino) -1- oxo propyl- 2- yl) t-butyl carbamate
At 20 DEG C, to (S) -2- ((tertbutyloxycarbonyl) amino) propionic acid (20mg, 0.106mmol)) in N, N- dimethyl methyl HATU (39mg, 0.103mmol) is added in solution in amide (1.3mL).By the reaction mixture in mutually synthermal stirring 30 Minute, 2- ((4- (amino methyl) benzyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- is added at this time Base) pyridine -3,5- dimethoxy nitrile dihydrochloride (synthesis, 50mg, 0.101mmol are described in embodiment 71) and triethylamine (0.042mL, 0.304mmol).After 20 DEG C are stirred overnight, which is filtered and is purified with reversed-phase HPLC (Gilson, 30mm x 50mm Gemini column, NH4OH modifying agent), obtain (S)-(1- ((4- (((3,5- dicyano -4- second Base -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2-l) sulfenyl) methyl) benzyl) amino) -1- oxo propyl- 2- Base) t-butyl carbamate (52mg, 87%) is pale solid.LCMS m/z=592 [M+H]+。
Step 2:(S) -2- amino-N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- diaza cycloheptyl Alkane -1- base) pyridine -2- base) sulfenyl) methyl) benzyl) propionamide
By (S)-(1- ((4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyrrole Pyridine -2- base) sulfenyl) methyl) benzyl) amino) -1- oxo propyl- 2- yl) t-butyl carbamate (30mg, 0.051mmol) exists Suspension in the dioxane of HCl (4M, 1.5mL, 6.0mmol) is stirred at room temperature 2 hours.Then by the reaction mixture Concentration.Resulting materials are suspended in methanol, it is free-basing with isopropylamine.The mixture reversed-phase HPLC is purified (Gilson, 30mm x 50mm Gemini column, NH4OH modifying agent), obtain (S) -2- amino-N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2-l) sulfenyl) methyl) benzyl) propionamide (23mg, 92%), be White solid.LCMS m/z=492 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.29 (t, J=6.08Hz, 1H), 7.30-7.38 (m, J=8.11Hz, 2H), 7.17-7.25 (m, J=8.11Hz, 2H), 4.47 (s, 2H), 4.25 (d, J= 5.83Hz, 2H), 3.81-3.94 (m, 4H), 3.28 (q, J=6.84Hz, 1H), 2.78 (q, J=7.44Hz, 2H), 2.60- 2.70 (m, 2H), 2.45-2.49 (m, 2H), 2.24 (s, 3H), 1.89-1.97 (m, 2H), 1.83 (br.s., 2H), 1.22 (t, J =7.60Hz, 3H), 1.14 (d, J=7.10Hz, 3H).
Embodiment 98
(R) -2- amino-N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- Base) pyridine -2- base) sulfenyl) methyl) benzyl) propionamide
Step 1:(R)-(1- ((4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- Base) pyridine -2- base) sulfenyl) methyl) benzyl) amino) -1- oxo propyl- 2- yl) t-butyl carbamate
At 20 DEG C, to (R) -2- ((tertbutyloxycarbonyl) amino) propionic acid (20mg, 0.106mmol)) in N, N- dimethyl methyl HATU (39mg, 0.103mmol) is added in solution in amide (1.3mL).By the reaction mixture in mutually synthermal stirring 30 Minute, 2- ((4- (amino methyl) benzyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- is added at this time Base) pyridine -3,5- dimethoxy nitrile dihydrochloride (synthesis, 50mg, 0.101mmol are described in embodiment 71) and triethylamine (0.042mL, 0.304mmol).Then the reaction mixture is stirred overnight at 20 DEG C.The reaction mixture is filtered and is used anti- Phase HPLC purifies (Gilson, 30mm x 50mm Gemini column, NH4OH modifying agent), obtain (R)-(1- ((4- (((3,5- bis- Cyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2-l) sulfenyl) methyl) benzyl) amino) -1- Oxo propyl- 2- yl) t-butyl carbamate (54mg, 90%) is pale solid.LCMS m/z=592 [M+H]+。
Step 2:(R) -2- amino-N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- diaza cycloheptyl Alkane -1- base) pyridine -2- base) sulfenyl) methyl) benzyl) propionamide
By (R)-(1- ((4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyrrole Pyridine -2- base) sulfenyl) methyl) benzyl) amino) -1- oxo propyl- 2- yl) t-butyl carbamate (34mg, 0.054mmol) exists Suspension in the dioxane of HCl (4M, 1.5mL, 6.0mmol) is stirred at room temperature 2 hours.Then by the reaction mixture Concentration.By resulting materials be suspended in methanol and with isopropylamine it is free-basing.The mixture reversed-phase HPLC is purified (Gilson, 30mmx50mm Gemini column, NH4OH modifying agent), obtain (R) -2- amino-N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2-l) sulfenyl) methyl) benzyl) propionamide (19mg, 72%), be White solid.LCMS m/z=492 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.29 (t, J=5.96Hz, 1H), 7.30-7.38 (m, J=8.11Hz, 2H), 7.17-7.25 (m, J=8.11Hz, 2H), 4.47 (s, 2H), 4.25 (d, J= 5.83Hz, 2H), 3.82-3.94 (m, 4H), 3.28 (q, J=6.84Hz, 1H), 2.78 (q, J=7.60Hz, 2H), 2.60- 2.69 (m, 2H), 2.45-2.48 (m, 2H), 2.24 (s, 3H), 1.89-1.99 (m, 2H), 1.83 (br.s., 2H), 1.22 (t, J =7.60Hz, 3H), 1.14 (d, J=6.84Hz, 3H).
Embodiment 99
1- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) benzyl) -3- ethyl urea
In room temperature, to 2- ((4- (amino methyl) benzyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- diaza cycloheptyl Alkane -1- base) pyridine -3,5- dimethoxy nitrile dihydrochloride (synthesis, 50mg, 0.101mmol are described in embodiment 71) He Sanyi Ethyl isocyanate (8.02 μ are added in amine (0.028mL, 0.203mmol) in the solution in n,N-Dimethylformamide (1.0mL) L, 0.101mmol).Then the reaction mixture is stirred at room temperature 2 hours.By the reaction mixture methanol dilution, filtering And purify (Gilson, 30mm x 50mm Gemini column, NH with reversed-phase HPLC4OH modifying agent), obtain 1- (4- (((3,5- bis- Cyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) methyl) benzyl) -3- ethyl urea (27mg, 54%), is pale solid.LCMS m/z=492 [M+H]+。1H NMR (400MHz, DMSO-d6)δppm 7.30-7.37 (m, J=8.11Hz, 2H), 7.16-7.23 (m, J=8.11Hz, 2H), 6.28 (t, J=5.96Hz, 1H), 5.88 (t, J=5.70Hz, 1H), 4.47 (s, 2H), 4.16 (d, J=6.08Hz, 2H), 3.82-3.94 (m, 4H), 3.02 (dq, J= 5.70,7.14Hz, 2H), 2.78 (q, J=7.60Hz, 2H), 2.60-2.69 (m, 2H), 2.44-2.49 (m, 2H), 2.24 (s, 3H), 1.89-1.97 (m, 2H), 1.22 (t, J=7.60Hz, 3H), 0.99 (t, J=7.10Hz, 3H).
Embodiment 100
1- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) benzyl) -3- phenylurea
1- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) benzyl) -3- phenylurea
In room temperature, to 2- ((4- (amino methyl) benzyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- diaza cycloheptyl Alkane -1- base) pyridine -3,5- dimethoxy nitrile dihydrochloride (synthesis, 50mg, 0.101mmol are described in embodiment 71) He Sanyi Solution of the amine (0.028mL, 0.203mmol) in n,N-Dimethylformamide (1.0mL) be added phenyl isocyanate (0.011mL, 0.101mmol).Then the reaction mixture is stirred at room temperature 2 hours.By the reaction mixture methanol dilution, filtering is simultaneously Purify (Gilson, 30mm x 50mm Gemini column, NH with reversed-phase HPLC4OH modifying agent), obtain 1- (4- (((3,5- dicyan Base -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) methyl) benzyl) -3- phenylurea (32mg, 59%), is pale solid.LCMS m/z=540 [M+H]+。1H NMR (400MHz, DMSO-d6)δppm 8.56 (s, 1H), 7.33-7.43 (m, 4H), 7.15-7.30 (m, 4H), 6.85-6.93 (m, 1H), 6.61 (t, J=5.96Hz, 1H), 4.48 (s, 2H), 4.27 (d, J=6.08Hz, 2H), 3.80-3.94 (m, 4H), 2.77 (q, J=7.60Hz, 2H), 2.59- 2.68 (m, 2H), 2.44-2.49 (m, 2H), 2.22 (s, 3H), 1.85-1.96 (m, 2H), 1.22 (t, J=7.60Hz, 3H).
Embodiment 101
N- (4- (((3,5- dicyano -6- (4- methyl-1,4- Diazesuberane -1- base) -4- (methylsulfany) pyrrole Pyridine -2- base) sulfenyl) methyl) benzyl) acetamide
By N- (4- (((6- amino -3,5- dicyano -4- (methylsulfany) pyridine -2- base) sulfenyl) methyl) benzyl) second Amide (synthesis, step 3,940mg, 2.451mmol are described in embodiment 91) and copper chloride (II) (515mg, It 3.83mmol) adds to round-bottomed flask and is suspended in acetonitrile (100mL).The mixture is heated to 40 DEG C and continues 5 minutes.It will be sub- Solution of the nitric acid tert-butyl ester (0.5mL, 4.22mmol) in acetonitrile (20mL) is added slowly in the mixture and by the mixture It is stirred 60 minutes at 50 DEG C.Lcms analysis indicates that the reaction stops；By nitrite tert-butyl (0.05mL) and CuCl2(50mg) adds Into the mixture of the heating and every 20min continues to monitor by LCMS.Nitrite tert-butyl (0.05mL) and CuCl is added2 (50mg) is until lcms analysis instruction starting material substantially completely exhausts (~10 repeat).By the mixture by small silicagel pad/It filters and is washed with EtOAc:EtOH 4:1.By filtrate 1- methyl-1,4- Diazesuberane (0.761mL, 6.13mmol) handled with DIPEA (1mL).The solution turned blue, by LCMS monitoring reaction until chloromethylated intermediate exhausts.This is molten Liquid concentration, then purifies the (0.1%NH of 0-50-100% for the residue reversed-phase column chromatography4OH aqueous solution is in acetonitrile Solution).Required fraction is merged, is concentrated, is then lyophilized, obtains N- (4- (((3,5- dicyano -6- (4- methyl-1,4- phenodiazine Trioxepane -1- base) -4- (methylsulfany) pyridine -2- base) sulfenyl) methyl) benzyl) acetamide (365mg, 0.759mmol, 31.0% yield).LCMS m/z=481.3 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.33 (t, J=5.83Hz, 1H) 7.34 (d, J=8.11Hz, 2H) 7.21 (d, J=8.11Hz, 2H) 4.47 (s, 2H) 4.21 (d, J=5.83Hz, 2H) 3.76-3.90 (m, 4H) 2.76 (s, 3H) 2.64 (br.s., 2H) 2.42-2.49 (m, 2H) 2.23 (s, 3H) 1.94 (d, J= 4.82Hz, 2H) 1.85 (s, 3H).
Embodiment 102
(E) -3- (4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl) benzene Base) acrylic acid, trifluoroacetate
Step 1:(E) -3- (4- (hydroxymethyl) phenyl) tert-butyl acrylate
(4- bromophenyl) methanol (2.12g, 11.33mmol), triphenylphosphine are sequentially added into 100mL round-bottomed flask (0.268g, 1.020mmol), acid chloride (II) (0.102g, 0.453mmol), triethylamine (20mL, 143mmol) and acrylic acid The tert-butyl ester (4.98mL, 34.0mmol).Then the reaction is heated at 90 DEG C.After 4 hours, which is checked and seen with LCMS Observe no starting material and product.The reaction is cooled to room temperature, is then passed throughPad filtering, is then concentrated under reduced pressure, Then successive loading is adjusted with hexane, is then transported in 100% hexane to 25g the and 10g Biotage Ultra column of the double-deck landfill It row 2 minutes, is then run 30 minutes in the hexane solution of the EtOAc of 0-50% gradient, isolates (E) -3- (4- (hydroxymethyl) Phenyl) tert-butyl acrylate (2.29g, 9.77mmol, 86% yield), for deep amber oil.LCMS m/z=179.0 [M+ H-isobutene]+。
Step 2:(E) -3- (4- (chloromethyl) phenyl) tert-butyl acrylate
By (E) -3- (4- (hydroxymethyl) phenyl) tert-butyl acrylate (502mg, 2.143mmol) in methylene chloride Solution in (20mL) is cooling in ice bath, and thionyl chloride (0.172mL, 2.357mmol) then is added, is then slowly added into Weak solution of the DIEA (0.412mL, 2.357mmol) in DCM (5mL).The reaction is stirred at room temperature 1 hour.By the reaction It is concentrated under reduced pressure, then direct loading to 10g Biotage Ultra column, is adjusted with hexane, then runs 2 points in 100% hexane Then clock is run 28 minutes with the hexane solution of the EtOAc of 0-25% gradient, isolates (E) -3- (4- (chloromethyl) phenyl) third Enoic acid ter-butyl ester (416mg, 1.646mmol, 77% yield) is stood solidification for oil.LCMS m/z=197.0 [M+H- Isobutene]+。
Step 3:(E) -3- (4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) first Base) phenyl) tert-butyl acrylate
It (is described in embodiment 3, step 3 to 2- chloro- 6- (dimethylamino) -4- ethylpyridine -3,5- dimethoxy nitrile Synthesize, 105mg, 0.447mmol) thioacetic acid potassium is added in the solution in n,N-Dimethylformamide (2.5mL) (66.4mg, 0.582mmol) and triethylamine (0.187mL, 1.342mmol).Then the reaction is heated 0.5 hour at 50 DEG C. Then (E) -3- (4- (chloromethyl) phenyl) tert-butyl acrylate (113mg, 0.447mmol) is added and continues heating 1 at 50 DEG C Hour.The reaction is cooled to room temperature, water (10mL) is then added and forms solid.The solid by filtration is separated, then It is dissolved in the n,N-Dimethylformamide of 1.5mL, then loading is adjusted with hexane, then existed to 25g Biotage Ultra column 100% hexane is run 2 minutes, is then run 28 minutes in the hexane solution of 0-35%EtOAc, is obtained required product fraction.It will Fraction containing required product merges, and is then concentrated under reduced pressure, obtains (E) -3- (4- (((3,5- dicyano -6- (dimethylaminos Base) -4- ethylpyridine -2- base) sulfenyl) methyl) phenyl) tert-butyl acrylate (168mg, 0.375mmol, 84% yield), For oil.LCMS m/z=449.3 [M+H]+。
Step 4:(E) -3- (4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) first Base) phenyl) acrylic acid, trifluoroacetate
To (E) -3- (4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl) benzene Base) trifluoroacetic acid (200 μ l, 2.60mmol) is added in tert-butyl acrylate (46mg, 0.103mmol) in methylene chloride Aqueous premix in (1.8mL).Then the solution is stirred at room temperature.After 4 hours, starting material is not observed.Then will The reaction is concentrated under reduced pressure, and obtains solid, acetonitrile (3mL) is added then with the solid that is suspended.Then by the solid by filtration point From obtaining (E) -3- (4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl) phenyl) Acrylic acid, trifluoroacetate (28mg, 0.055mmol, 53.9% yield), is white solid.LCMS m/z=393.2 [M+ H]+。1H NMR (400MHz, DMSO-d6) δ ppm 12.43 (b, 1H), 7.65 (d, J=8.11Hz, 2H), 7.56 (d, J= 15.97Hz, 1H), 7.45 (d, J=8.11Hz, 2H), 6.51 (d, J=15.97Hz, 1H), 4.55 (s, 2H), 3.32 (s, 6H), 2.77 (q, J=7.60Hz, 2H), 1.21 (t, J=7.60Hz, 3H).
Embodiment 103
N- (4- (((3,5- dicyano -4- ethyl -6- ((2- hydroxyethyl) (methyl) amino) pyridine -2- base) sulfenyl) Methyl) benzyl) acetamide
The chloro- 4- ethyl -6- of step 1:2- ((2- hydroxyethyl) (methyl) amino) pyridine -3,5- dimethoxy nitrile
At 0 DEG C, to chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (synthesis is described in embodiment 3, step 2, 2.25g, 9.99mmol) addition triethylamine (4.18mL, 30mmol) in the solution in methylene chloride (30mL), 2- is then added (methylamino) ethyl alcohol (750mg, 9.99mmol).The mixture is warmed to 25 DEG C and is stirred 16 hours.The mixture is fallen Enter in water and is extracted with methylene chloride (2x 25mL).The organic phase is concentrated under reduced pressure, then by the residue column chromatography Purifying (uses methylene chloride: methanol 100:1 elution), obtains the chloro- 4- ethyl -6- of 2- ((2- hydroxyethyl) (methyl) amino) pyrrole Pyridine -3,5- dimethoxy nitrile (2.3g, 8.69mmol, 87% yield).LCMS m/z=265.0 [M+H]+。
Step 2: acetic acid 4- (acetylamino methyl) benzyl ester
At 0 DEG C, to (4- (amino methyl) phenyl) solution of the methanol (19g, 139mmol) in tetrahydrofuran (150mL) Then chloroacetic chloride (21.6mL, 305mmol) is added dropwise in middle addition triethylamine (57.9mL, 416mmol).Then by the mixture temperature Heat is to 25 DEG C and stirs 16 hours.The mixture is concentrated under reduced pressure, the residue is then allocated in water (40mL) and acetic acid second Between ester (60mL).The organic phase is separated and is concentrated to get crude acetic acid 4- (acetylamino methyl) benzyl ester (26g) .LCMS M/z=443.1 [2M+H]+, 222.1 [M+H]+(secondary).
Step 3:N- (4- (hydroxymethyl) benzyl) acetamide
At 0 DEG C, to acetic acid 4- (acetylamino methyl) benzyl ester (26g, 118mmol) in tetrahydrofuran (80mL) Water (40mL) and lithium hydroxide (8.44g, 353mmol) are added in solution.The mixture is stirred 16 hours at 25 DEG C.This is mixed Object evaporation is closed to remove tetrahydrofuran and extract the residue ethyl acetate (2x 50mL).The organic phase is concentrated and is used in combination Ethyl acetate washing, obtains N- (4- (hydroxymethyl) benzyl) acetamide (8.7g, 48.5mmol, 41% yield), is pale yellow Color solid.1H NMR (400MHz, DMSO-d6) δ ppm 8.33 (brs, 1H), 7.26 (d, J=8Hz, 2H), 7.20 (d, J= 8Hz, 2H), 5.16 (t, J=6Hz, 1H), 4.47 (d, J=8Hz, 2H), 4.22 (d, J=4Hz, 2H), 1.87 (s, 3H).
Step 4:N- (4- ((3,5- dicyano -4- ethyl -6- ((2- hydroxyethyl) (methyl) amino) pyridine -2- base sulphur Base) methyl) benzyl) acetamide
At 0 DEG C, to N- (4- (hydroxymethyl) benzyl) acetamide (930mg, 5.19mmol) in methylene chloride (30mL) Suspension in be added carbon tetrabromide (1893mg, 5.71mmol), then be added triphenylphosphine (1497mg, 5.71mmol).It will The mixture is warmed to 25 DEG C and stirs 16 hours.The mixture is poured into water (20mL).Separation organic phase will simultaneously depressurize dense Contracting, obtains raw product, it is purified with column chromatography, and then use petroleum ether: ethyl acetate (3:1,50mL) washing obtains crude N- (4- (bromomethyl) benzyl) acetamide (1.4g).To the chloro- 4- ethyl -6- of 2- ((2- hydroxyethyl) (methyl) amino) pyrrole Thioacetic acid is added in the solution in n,N-Dimethylformamide (15mL) in pyridine -3,5- dimethoxy nitrile (264mg, 0.997mmol) Then potassium carbonate (414mg, 2.99mmol) is added in potassium (171mg, 1.496mmol).The mixture is small in 25 DEG C of stirrings 16 When, potassium carbonate (474mg, 1.144mmol) and crude N- (4- (bromomethyl) benzyl) acetamide (435mg) is then added.It will The mixture stirs 16 hours at 25 DEG C.The mixture is poured into water (15mL) and is extracted with ethyl acetate (2x 25mL).It should Organic phase is concentrated under reduced pressure, and obtains raw product, it is purified (methylene chloride: methanol 30:1) with column chromatography, then from first It is recrystallized in alcohol, obtains N- (4- (((3,5- dicyano -4- ethyl -6- ((2- hydroxyethyl) (methyl) amino) pyridine -2- base) Sulfenyl) methyl) benzyl) acetamide (300mg, 0.708mmol) .LCMS m/z=424.3 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.33 (brs, 1H), 7.35 (d, J=8Hz, 2H), 7.21 (d, J=8Hz, 2H), 4.88 (t, J=6Hz, 1H), 4.47 (s, 2H), 4.22 (d, J=4Hz, 2H), 3.86 (t, J=4Hz, 2H), 3.64 (d, J=4Hz, 2H), 3.41 (s, 3H), 2.77 (m, 2H), 1.86 (s, 3H), 1.21 (t, J=8Hz, 3H).
Embodiment 104
4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) methyl)-N- methyl benzenesulfonamide
To N, N- bromine is added in 4- dimethyl benzene sulfonamide (1g, 5.40mmol) in the solution in carbon tetrachloride (10mL) Succinimide (0.961g, 5.40mmol) and benzoyl peroxide (0.065g, 0.270mmol).Bottle is closed the lid Son heats 5 hours at 110 DEG C.The reaction is cooled to room temperature, 4- (bromomethyl)-N- methyl benzenesulfonamide crude solution is obtained. Then by the thick material solution by portions of 4- (bromomethyl)-N- methyl benzenesulfonamide add to 4- ethyl -2- sulfydryl -6- (4- methyl-1, 4- Diazesuberane -1- base) pyridine -3,5- dimethoxy nitrile (describe synthesis in embodiment 69, step 1,180mg, It is true up to passing through lcms analysis 0.597mmol) with the solution being prepared separately of DIEA (209 μ l, 1.194mmol) in chloroform Fixed all starting mercaptan is depleted.The reaction is stirred 1 hour, be concentrated and remaining crude mixture is allocated in acetic acid Between ethyl ester and water.Separate each layer and organic layer is dry and be concentrated under reduced pressure.By raw product silica gel chromatography (12g silicon Rubber column gel column, with 100% ethyl acetate elute, then with 10-70% gradient (26% ethyl alcohol/ethyl acetate, contain 0.1% hydrogen-oxygen Change ammonium) ethyl acetate solution elution, obtain 4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- diaza cycloheptyls Alkane -1- base) pyridine -2- base) sulfenyl) methyl)-N- methyl benzenesulfonamide (60mg, 20% yield) LCMS m/z=485.6 [M+ H]+。1H NMR (400MHz, methanol-d4) δ ppm 7.82 (d, J=8.4Hz, 2H), 7.55 (d, J=8.4Hz, 2H), 4.61 (s, 2H), 3.84-4.02 (m, 4H), 2.93 (q, J=7.6Hz, 2H), 2.68-2.75 (m, 2H), 2.58-2.65 (m, 2H), 2.53 (s, 3H), 2.36 (s, 3H), 1.97-2.11 (m, 2H), 1.33 (t, J=7.60Hz, 3H).
Embodiment 105
N- (4- (((3,5- dicyano -4- ethyoxyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) methyl) benzyl) acetamide
Step 1:2- (diethoxy methylene) malononitrile
By ethylene -1,1,2,2- tetra- formonitrile HCNs (6.1g, 47.6mmol) and urea (0.858g, 14.29mmol) add to round bottom burning Bottle is simultaneously suspended in ethyl alcohol (40mL, 773mmol).The mixture is heated 50 minutes at 40 DEG C.The solution is cooled to room temperature, It is subsequently cooled to -78 DEG C and stirs 30 minutes, for the pale precipitation formed.Cooling suspension is filtered, by the precipitating It is collected by filtration and is washed with cold ether, obtain 2- (diethoxy methylene) malononitrile (2.5g, 15.04mmol, 31% Yield).LCMS m/z=166.9 [M+H]+。
The chloro- 4- ethoxy pyridine -3,5- dimethoxy nitrile of step 2:2- amino -6-
Malononitrile (1.10g, 16.65mmol) and potassium tert-butoxide (2.0g, 17.82mmol) are added into round-bottomed flask and mixed It is suspended from ethyl alcohol (100mL).The mixture is heated 5 minutes at 45 DEG C.By 2- (diethoxy methylene) malononitrile (2.5g, 15.04mmol) solution in EtOH (10mL) is added slowly in the mixture and is heated to reflux the reaction 1.5 hours.So The reaction mixture is filtered afterwards and the filter vacuum is concentrated.Then to be successively added in surplus material acetone (100mL) and Concentrated hydrochloric acid (15mL).The mixture is stirred 2 hours at 50 DEG C, is cooled to room temperature, is then cooled further to 0 DEG C.It will be formed Precipitating be collected by filtration, obtain chloro- 4- ethoxy pyridine -3, the 5- dimethoxy nitrile of 2- amino -6- (2.3g, 10.33mmol, 69% yield).LCMS m/z=223.0,225.0 [M+H]+。
Step 3:2- amino -4- ethyoxyl -6- mercaptopyridine -3,5- dimethoxy nitrile
By chloro- 4- ethoxy pyridine -3, the 5- dimethoxy nitrile (767mg, 3.45mmol) of 2- amino -6- and thioacetic acid potassium (600mg, 5.25mmol) adds to round-bottomed flask and is suspended in ethyl alcohol (50mL).It is added triethylamine (1.5mL, 10.76mmol) And the mixture is stirred at room temperature 4 hours.Additional thioacetic acid potassium (201mg) is added and stirs the reaction 1 hour.So Last a thioacetic acid potassium (311mg) is added afterwards and is stirred overnight the reaction.It is formed and precipitates and the mixture is cooled to 0 ℃.The solid by filtration is collected to and used ether/heptane wash, obtains 2- amino -4- ethyoxyl -6- mercaptopyridine -3,5- Dimethoxy nitrile (1.26g), is crude solid.Using the material without being further purified.LCMS m/z=221.0 [M+H]+。
Step 4:4- (((6- amino -3,5- dicyano -4- ethoxy pyridine -2- base) sulfenyl) methyl) benzylamino first Tert-butyl acrylate
By 2- amino -4- ethyoxyl -6- mercaptopyridine -3,5- dimethoxy nitrile (1.275g；By crude material obtained in the previous step Material) and sodium bicarbonate aqueous solution (1.05g, 12.50mmol) add to round-bottomed flask and be suspended in n,N-Dimethylformamide In (30mL).4- (bromomethyl) the benzylcarbamate tert-butyl ester (2g, 6.66mmol) is slowly added into the mixture and should Reaction is stirred at room temperature 1 hour.The mixture is allocated between ethyl acetate and saturated sodium chloride solution.It separates each layer and incites somebody to action Aqueous layer with ethyl acetate (3x) back extraction.Combined organic layer is washed with saturated sodium chloride solution, is dried, filtered with magnesium sulfate And it is concentrated.Gained yellow oil is ground with DCM/ heptane and the precipitating is collected by filtration, obtains 4- (((6- amino -3,5- Dicyano -4- ethoxy pyridine -2- base) sulfenyl) methyl) the benzylcarbamate tert-butyl ester (2.54g, 3.47mmol, 60%) .LCMS m/z=440.3 [M+H]+。
Step 5:2- amino -6- ((4- (amino methyl) benzyl) sulfenyl) -4- ethoxy pyridine -3,5- dimethoxy nitrile hydrochloric acid Salt
By 4- (((6- amino -3,5- dicyano -4- ethoxy pyridine -2- base) sulfenyl) methyl) benzylcarbamate uncle Butyl ester (2.54g, 3.47mmol) and HCI solution (18mL, 72.0mmol；The 1,4- dioxane of 4N) add to round bottom burning Bottle simultaneously stirs 15 minutes at 50 DEG C.The mixture is concentrated in vacuo, is suspended in ethylacetate/ether and by solid by filtration It collects.Then by solid ether/heptane wash, crude 2- amino -6- ((4- (amino methyl) benzyl) sulfenyl)-is obtained 4- ethoxy pyridine -3,5- dimethoxy nitrile hydrochloride (2.4g).Using the material without being further purified.LCMS m/z= 340.2[M+H]+。
Step 6:N- (4- (((6- amino -3,5- dicyano -4- ethoxy pyridine -2- base) sulfenyl) methyl) benzyl) second Amide
By 2- amino -6- ((4- (amino methyl) benzyl) sulfenyl) -4- ethoxy pyridine -3,5- dimethoxy nitrile hydrochloride (900mg, by crude material obtained in the previous step) be suspended in methylene chloride (20mL) and be added triethylamine (0.831mL, 5.96mmol) and acetic anhydride (0.197mL, 2.087mmol).The mixture is stirred at room temperature 15 minutes.By the suspension liquid cooling But to 0 DEG C, filter and by the solid of collection ether/heptane wash, obtain crude N- (4- (((6- amino -3,5- dicyan Base -4- ethoxy pyridine -2- base) sulfenyl) methyl) benzyl) acetamide (999mg).Using the material without being further purified. LCMS m/z=382.2 [M+H]+。
Step 7:N- (4- (((the chloro- 3,5- dicyano -4- ethoxy pyridine -2- base of 6-) sulfenyl) methyl) benzyl) acetyl Amine
By N- (4- (((6- amino -3,5- dicyano -4- ethoxy pyridine -2- base) sulfenyl) methyl) benzyl) acetamide (999mg, from crude material obtained in the previous step) and copper chloride (II) (600mg, 4.46mmol) add to round-bottomed flask and are suspended In acetonitrile (100mL).The mixture is heated to 40 DEG C of lasting 5min.Nitrite tert-butyl (0.575mL, 4.85mmol) is slow Slowly it adds to the mixture and stirs the mixture 4 hours at 50 DEG C.By the nitrite tert-butyl (0.1mL) of additional quantity and CuCl2(150mg) adds to the mixture of the heating and stirs 1 hour.The nitrite tert-butyl of last part is added (0.15mL) and CuCl2(220mg).After 1 hour, which is judged whether to complete by lcms analysis.The mixture is led to Too small silicagel pad/Filter and with ethyl acetate: ethyl alcohol 4:1 is washed.The filtrate is concentrated, N- (4- (((6- is obtained Chloro- 3,5- dicyano -4- ethoxy pyridine -2- base) sulfenyl) methyl) benzyl) (660mg, 1.399mmol, 53% are produced acetamide Rate), for burnt orange/brown solid.LCMS m/z=401.1,403.1 [M+H]+。
Step 8:N- (4- (((3,5- dicyano -4- ethyoxyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyrrole Pyridine -2- base) sulfenyl) methyl) benzyl) acetamide
By N- (4- (((the chloro- 3,5- dicyano -4- ethoxy pyridine -2- base of 6-) sulfenyl) methyl) benzyl) acetamide (60mg, 0.127mmol) and 1- methyl-1,4- Diazesuberane (0.1mL, 0.806mmol) add in bottle.Tetrahydro is added Simultaneously the mixture is stirred at room temperature 15 minutes by furans (12mL) and DIPEA (0.1mL, 0.573mmol).By the reaction mixture Concentration.Remaining residue reversed-phase column chromatography is purified into (0-40-50-100%0.1%NH4OH aqueous solution/acetonitrile) and freeze It is dry, obtain N- (4- (((3,5- dicyano -4- ethyoxyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) benzyl) acetamide (19mg, 0.039mmol, 30%) is white solid.LCMS m/z=479.3 [M+H] +。1H NMR (400MHz, DMSO-d6) δ ppm 8.33 (t, J=6.0Hz, 1H), 7.34 (d, J=8.1Hz, 2H), 7.21 (d, J =8.1Hz, 2H), 4.55 (q, J=6.8Hz, 2H), 4.46 (s, 2H), 4.21 (d, J=6.1Hz, 2H), 3.92-3.78 (m, 4H), 2.70-2.58 (m, 2H), 2.46-2.38 (m, 2H), 2.23 (s, 3H), 1.98-1.87 (m, 2H), 1.86 (s, 3H), 1.37 (t, J=7.1Hz, 3H).
Embodiment 106
2- ({ 3,5- dicyano -4- ethyl -6- [4- (2- methoxy ethyl) -1,4- Diazesuberane -1- base] pyrrole Pyridine -2- base } sulfanyl) -2- phenyl-acetamides
Step 1:2- ((3,5- dicyano -6- (1,4- Diazesuberane -1- base) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides
To 2- [(the bromo- 3,5- dicyano -4- ethyl -2- pyridyl group of 6-) sulfanyl] -2- phenvl-acetamide (such as embodiment 6, synthesis described in step 1,500mg, 1.25mmol) Isosorbide-5-Nitrae-phenodiazine is added in the solution in tetrahydrofuran (25mL) Trioxepane (1.57g, 15.64mmol).The reaction mixture is stirred at room temperature 15 minutes.By the solvent concentration, starched Liquid is allocated between EtOAc (100mL) and water (100mL).It separates each phase and washs water phase with EtOAc (100mL). Combined organic matter water (150mL), salt water (150mL) are washed, filtered by Hydrophobic glass funnel and by the solvent under reduced pressure It removes.By gained residue triturated under ether, filtering is washed and dry with ether (25mL).Raw product is dissolved in 10% MeOH/CH2Cl2, it is adsorbed in SiO2(3g) and (12g RediSep column, using 20%, (MeOH contains 5% with silica gel chromatography NH3) CH2Cl2Solution obtains 2- [[3,5- dicyano -6- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -4- second as eluant, eluent Base -2- pyridyl group] sulfanyl] -2- phenvl-acetamide (339mg, 65% yield) is light yellow solid.LCMS m/z= 419.2[M–H]–。
Step 2:2- ({ 3,5- dicyano -4- ethyl -6- [4- (2- methoxy ethyl) -1,4- Diazesuberane -1- Base] pyridine -2- base } sulfanyl) -2- phenyl-acetamides
To 2- [[3,5- dicyano -6- (1,4- Diazesuberane -1- base) -4- ethyl -2- pyridyl group] sulfanyl] - 2- phenvl-acetamide (30mg, 0.07mmol) be added in the solution in acetonitrile (3mL) 2- bromo-ethyl-methyl ether (0.013mL, 0.14mmol), n,N-diisopropylethylamine (0.035mL, 0.21mmol) then is added.The reaction mixture is stirred at 65 DEG C 5 hours, 2- bromo-ethyl-methyl ether (0.033mL, 0.36mmol) is further then added and is reheated 17 hours at 65 DEG C.It should Product mixtures are cooling, and water (7.5mL) is then added and stirs the mixture 30 minutes, filtering is washed with water (2x 10mL) And it is dried in vacuo at 50 DEG C.Raw product is adsorbed in SiO2(0.7g) and (4g RediSep column uses with silica gel chromatography 20% (MeOH contains 5%NH3) DCM solution), obtain 2- [[3,5- dicyano -4- ethyl -6- [4- (2- methoxyl group second Base)-Isosorbide-5-Nitrae-Diazesuberane -1- base] -2- pyridyl group] sulfanyl] -2- phenvl-acetamide (25mg, 73% yield), be White solid.LCMS m/z=477.3 [M-H]–。1H NMR (300MHz, DMSO-d6) δ ppm 7.91 (s, 1H), 7.52-7.31 (m, 6H), 5.51 (s, 1H), 3.97-3.81 (m, 4H), 3.43-3.38 (m, 2H), 3.23 (s, 3H), 2.87-2.68 (m, 4H), 2.67-2.56 (m, 4H), 1.89 (m, 2H), 1.21 (t, J=7.6Hz, 3H).
Embodiment 107
2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxypropyl) -1,4- Diazesuberane -1- base) pyridine - 2- yl) sulfenyl) -2- phenyl-acetamides
To 2- [[3,5- dicyano -6- (1,4- Diazesuberane -1- base) -4- ethyl -2- pyridyl group] sulfanyl] - Solution of the 2- phenvl-acetamide (synthesis, 30mg, 0.07mmol are described in embodiment 106, step 1) in acetonitrile (3mL) Middle addition 1- bromine propan-2-ol (0.013mL, 0.14mmol), then be added n,N-diisopropylethylamine (0.035mL, 0.21mmol).By the reaction mixture 65 DEG C stir 5 hours, then further be added 1- bromine propan-2-ol (0.064mL, 0.70mmol) and at 65 DEG C reheat 17 hours.The product mixtures are cooled to environment temperature, are added water (7.5mL), stirring 30 minutes, filtering was washed with water (2x 10mL) and is dried in vacuo at 50 DEG C.Raw product is adsorbed in SiO2(0.7g) is used in combination Silica gel chromatography (4g RediSep column), using 10%, (MeOH contains 5%NH3) CH2Cl2Solution is obtained as eluant, eluent 2- [[3,5- dicyano -4- ethyl -6- [4- (2- hydroxypropyl) -1,4- Diazesuberane -1- base] -2- pyridyl group] sulfane Base] -2- phenvl-acetamide (21mg, 62% yield) is white solid.LCMS m/z=477.3 [M-H]–。1H NMR (300MHz, DMSO-d6) δ ppm 7.91 (s, 1H), 7.54-7.45 (m, 2H), 7.43-7.30 (m, 4H), 5.51 (s, 1H), 4.27 (d, J=3.9Hz, 1H), 4.01-3.80 (m, 4H), 3.79-3.58 (m, 1H), 2.90-2.69 (m, 4H), 2.68-2.53 (m, 2H), 2.47-2.22 (m, 2H), 1.89 (br s, 2H), 1.21 (t, J=7.6Hz, 3H), 1.01 (d, J=6.0Hz, 3H).
Embodiment 108
2- [4- (6- { [carbamoyl (phenyl) methyl] sulfanyl } -3,5- dicyano -4- ethylpyridine -2- base) - 1,4- Diazesuberane -1- base] methyl acetate
To 2- [[3,5- dicyano -6- (1,4- Diazesuberane -1- base) -4- ethyl -2- pyridyl group] sulfanyl] - Solution of the 2- phenvl-acetamide (synthesis, 30mg, 0.07mmol are described in embodiment 106, step 1) in acetonitrile (3mL) Middle addition methyl chloroacetate (0.013mL, 0.14mmol), then be added n,N-diisopropylethylamine (0.035mL, 0.21mmol).By the reaction mixture 65 DEG C stir 1 hour and be added additional methyl chloroacetate (0.013mL, 0.14mmol), n,N-diisopropylethylamine (0.035mL, 0.21mmol) then is added.By mixture reheating 2 hours, so Additional methyl chloroacetate (0.013mL, 0.14mmol) is added afterwards, then be added n,N-diisopropylethylamine (0.035mL, 0.21mmol).After heating 10 hours in total, which is cooled to environment temperature, water (7.5mL) is added and mixes this It closes object to stir 30 minutes, filtering, be washed with water (2x 10mL) and is dried in vacuo at 50 DEG C.By raw product loading to SiO2, make With methylene chloride and a small amount of methanol and with silica gel chromatography (4g RediSep column), using 5%, (MeOH contains 5%NH3) CH2Cl2Solution obtains 2- [4- [6- (2- amino -2- oxo -1- phenyl-ethyl group) sulfanyl -3,5- dicyano-as eluant, eluent 4- ethyl -2- pyridyl group]-Isosorbide-5-Nitrae-Diazesuberane -1- base] methyl acetate (23mg, 65% yield) is white solid. LCMS m/z=491.3 [M-H]–。1H NMR (300MHz, DMSO-d6) δ ppm 7.91 (s, 1H), 7.52-7.30 (m, 6H), 5.51 (s, 1H), 3.97-3.84 (m, 4H), 3.62 (s, 3H), 3.49-3.35 (m, 2H), 2.96-2.84 (m, 2H), 2.81- 2.71 (m, 4H), 1.88 (br s, 2H), 1.21 (t, J=7.6Hz, 3H).
Embodiment 109
2- { [3,5- dicyano -4- cyclopropyl -6- (4- methyl -5- oxo -1,4- Diazesuberane -1- base) pyridine - 2- yl] sulfanyl } -2- phenyl-acetamides
The chloro- 4- cyclopropyl -6- of step 1:2- (4- methyl -5- oxo -1,4- Diazesuberane -1- base) pyridine -3,5- Dimethoxy nitrile
To chloro- 4- cyclopropyl pyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (synthesis is described in embodiment 4, step 2, 300mg, 1.260mmol) 4- methyl-1,4- diaza cycloheptyl are added in the solution in n,N-Dimethylformamide (10mL) Alkane -5- ketone (162mg, 1.260mmol) and triethylamine (0.176mL, 1.260mmol).The reaction mixture is stirred at room temperature 1 Hour.Water is added in the reaction, which is filtered and dried, obtains the chloro- 4- cyclopropyl -6- of 2- (4- methyl -5- oxo - Isosorbide-5-Nitrae-Diazesuberane -1- base) pyridine -3,5- dimethoxy nitrile (350mg) is solid.LCMS m/z=329.8 [M+H]+。
Step 2:2- { [3,5- dicyano -4- cyclopropyl -6- (4- methyl -5- oxo -1,4- Diazesuberane -1- Base) pyridine -2- base] sulfanyl } -2- phenyl-acetamides
By the chloro- 4- cyclopropyl -6- of 2- (4- methyl -5- oxo -1,4- Diazesuberane -1- base) pyridine -3,5- diformazan Nitrile (350mg, 1.061mmol) and thioacetic acid potassium (145mg, 1.274mmol) are in n,N-Dimethylformamide (10mL) It is stirred at room temperature in solution 30 minutes.Then be added methanesulfonic acid 2- amino -2- oxo -1- phenylethylester (292mg, 1.274mmol) and Et3N (0.296mL, 2.123mmol).The reaction mixture is stirred at room temperature overnight.It is anti-that water is added to this In answering and obtained solid is filtered and used flash column chromatography (being eluted with DCM:MeOH 20:1), obtains 2- { [3,5- dicyan Base -4- cyclopropyl -6- (4- methyl -5- oxo -1,4- Diazesuberane -1- base) pyridine -2- base] sulfanyl } -2- phenyl second Amide (192.5mg), is solid.LCMS m/z=460.6 [M+H]+。1H NMR (400MHz, CDCl3)δppm 7.52– 7.45 (m, 2H), 7.44-7.36 (m, 3H), 6.75 (br s, 1H), 5.79 (br s, 1H), 5.44 (s, 1H), 4.10-3.90 (m, 4H), 3.75-3.62 (m, 2H), 3.08-2.91 (m, 5H), 2.18-2.06 (m, 1H), 1.37-1.28 (m, 2H), 1.23- 1.13 (m, 2H).
Embodiment 110
2- { [3,5- dicyano -4- cyclopropyl -6- (5- oxo -1,4- Diazesuberane -1- base) pyridine -2- base] sulphur Alkyl } -2- phenyl-acetamides
The chloro- 4- cyclopropyl -6- of step 1:2- (5- oxo -1,4- Diazesuberane -1- base) pyridine -3,5- dimethoxy nitrile
In room temperature, (conjunction is described in embodiment 4, step 2 to chloro- 4- cyclopropyl pyridine -3, the 5- dimethoxy nitrile of 2,6- bis- Isosorbide-5-Nitrae-Diazesuberane -5- ketone is added in the solution in n,N-Dimethylformamide (10mL) at 237mg, 1mmol) (114mg, 1mmol), is then added Et3N (0.14mL, 1mmol).The mixture is stirred at room temperature 50 minutes, water is then used Dilution.The solid by filtration of precipitation is collected and is passed through silica gel chromatography (DCM:MeOH 20:1), the chloro- 4- of 2- is obtained Cyclopropyl -6- (5- oxo-Isosorbide-5-Nitrae-Diazesuberane -1- base) pyridine -3,5- dimethoxy nitrile (200mg, 55%) .LCMS m/z= 316.0[M+H]+。
Step 2:2- { [3,5- dicyano -4- cyclopropyl -6- (5- oxo -1,4- Diazesuberane -1- base) pyridine - 2- yl] sulfanyl } -2- phenyl-acetamides
By the chloro- 4- cyclopropyl -6- of 2- (5- oxo -1,4- Diazesuberane -1- base) pyridine -3,5- dimethoxy nitrile The solution of (200mg, 0.55mmol) and KSAc (75mg, 0.66mmol) in n,N-Dimethylformamide (6mL) is stirred in room temperature It mixes 30 minutes, then by methanesulfonic acid 2- amino -2- oxo -1- phenylethylester (151mg, 0.66mmol) and Et3N (0.15mL, It 1.1mmol) adds in the solution.The mixture is stirred at room temperature overnight, is then diluted with water.The solid of precipitation was passed through Filter collects and by silica gel chromatography (DCM:MeOH 10:1), obtains 2- { [3,5- dicyano -4- cyclopropyl -6- (5- oxygen Generation-Isosorbide-5-Nitrae-Diazesuberane -1- base) pyridine -2- base] sulfanyl } -2- phenyl-acetamides (76mg, 31%) .LCMS m/z= 446.8[M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.91 (s, 1H), 7.74-7.69 (m, 1H), 7.55-7.46 (m, 2H), 7.44-7.30 (m, 4H), 5.50 (s, 1H), 4.03-3.83 (m, 4H), 3.36-3.32 (m, 2H), 2.74-2.61 (m, 2H), 2.17-2.08 (m, 1H), 1.19-1.08 (m, 2H), 1.02-0.91 (m, 2H).
Embodiment 111
2- { [3,5- dicyano -4- ethyl -6- (4- methyl -5- oxo -1,4- Diazesuberane -1- base) pyridine -2- Base] sulfanyl } -2- phenyl-acetamides
To 2- [(the bromo- 3,5- dicyano -4- ethyl -2- pyridyl group of 6-) sulfanyl] -2- phenvl-acetamide (in embodiment 6, describe synthesis, 35mg, 0.09mmol in step 1) and triethylamine (0.03mL, 0.19mmol) in tetrahydrofuran (2mL) Solution in be added 4- methyl-1,4- Diazesuberane -5- keto hydrochloride (16mg, 0.10mmol).By the reaction mixture It is stirred at room temperature 1.5 hours.The mixture is diluted with EtOAc (20mL), is washed with water (20mL), by water phase EtOAc Merging is simultaneously slightly taken object to be washed with salt water (2x 25mL) by (20mL) washing, is filtered by Hydrophobic glass funnel and by the solvent It is removed under reduced pressure.It is dried in vacuo by the residue triturated under ether and at 50 DEG C, obtains 2- [[3,5- dicyano -4- ethyl -6- (4- Methyl -5- oxo-Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- pyridyl group] sulfanyl] (17mg, 43% produces -2- phenvl-acetamide Rate), it is yellow solid.LCMS m/z=447.2 [M-H]–.1H NMR (300MHz, DMSO-d6) δ ppm 7.93 (s, 1H), 7.54-7.31 (m, 6H), 5.54 (s, 1H), 4.13-3.90 (m, 4H), 3.64 (br s, 2H), 2.89-2.74 (m, 7H), 1.22 (t, J=7.6Hz, 3H).
Embodiment 112
2- { [3,5- dicyano -6- (1,4- Diazesuberane -1- base) -4- ethylpyridine -2- base] sulfanyl } -2- Phenyl-acetamides
Step 1:4- [6- (2- amino -2- oxo -1- phenyl-ethyl group) sulfanyl -3,5- dicyano -4- ethyl -2- pyrrole Piperidinyl] -1,4- Diazesuberane -1- carboxylate
By 2- [(the bromo- 3,5- dicyano -4- ethyl -2- pyridyl group of 6-) sulfanyl] -2- phenvl-acetamide (in embodiment 6, synthesis, 117mg, 0.29mmol are described in step 1) solution N1-Boc-1,4- diaza in tetrahydrofuran (3mL) Cycloheptane (0.12mL, 0.64mmol) is handled and is stirred at room temperature 3 hours.By the product mixtures loading to SiO2(0.9g) simultaneously With silica gel chromatography (12g RediSep column, with the CH of 0-10%MeOH2Cl2Solution elution), obtain 4- [6- (2- amino -2- Oxo -1- phenyl-ethyl group) sulfanyl -3,5- dicyano -4- ethyl -2- pyridyl group] -1,4- Diazesuberane -1- formic acid uncle Butyl ester (118mg, 77% yield) is colourless glass object.LCMS m/z=519 [M-H]–。
Step 2:2- { [3,5- dicyano -6- (1,4- Diazesuberane -1- base) -4- ethylpyridine -2- base] sulfane Base } -2- phenyl-acetamides, hydrochloride
By 4- [6- (2- amino -2- oxo -1- phenyl-ethyl group) sulfanyl -3,5- dicyano -4- ethyl -2- pyridine Base]-Isosorbide-5-Nitrae-Diazesuberane -1- carboxylate (111mg, 0.21mmol) is in CH2Cl2Solution 2M in (0.5mL) The diethyl ether solution (0.3mL, 0.6mmol) and MeOH (2mL) of HCl is handled, and then the ether with the 2M HCl of another part is molten Liquid (0.7mL, 1.4mmol) is handled and is stirred at room temperature 18 hours.By the solution by being concentrated by evaporation at 45 DEG C to 1mL volume, Then it is handled 30 minutes with the methanol solution (1mL) of 3M HCl, is then concentrated.By the residue triturated under ether and it is evaporated to It is dry, obtain 2- [[3,5- dicyano -6- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -4- ethyl -2- pyridyl group] sulfanyl] -2- benzene Base-acetamide hydrochloride (87mg, 89% yield), is faint yellow solid.LCMS m/z=419.2 [M-H]–。1H NMR (300MHz, DMSO-d6) δ ppm 9.11 (br s, 2H), 8.01 (s, 1H), 7.55-7.31 (m, 6H), 5.51 (s, 1H), 4.23-4.10 (m, 2H), 4.10-3.87 (m, 2H), 3.30-3.12 (m, 3H), 2.93-2.68 (m, 2H), 2.18 (br s, 2H), 1.22 (t, J=7.5Hz, 3H).
Embodiment 113
2- ({ 3,5- dicyano -6- [4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base] -4- (2,2,2- tri- Fluoro ethyl) pyridine -2- base } sulfanyl) -2- phenyl-acetamides
Step 1:2- ((6- amino -3,5- dicyano -4- (2,2,2- trifluoroethyl) pyridine -2- base) sulfenyl) -2- phenyl Acetamide
By 3,3,3- trifluoropropyl aldehyde hydrates (0.31mL, 3.08mmol), N-methylmorpholine (0.68mL, 6.15mmol) It mixes and is dissolved in ethyl alcohol (10mL) with 2- cyano-thioacetamide (0.62g, 6.15mmol).By gained orange solution in environment Temperature stirs 72 hours.The product mixtures are concentrated under reduced pressure and attempt to be lost with ethyl alcohol/isohexane/ether mixtures crystallization It loses, obtains required product, be solid, obtain orange oil (282mg), be employed without and be further purified.By the oil Solution of the chloro- 2- phenvl-acetamide (121mg, 0.72mmol) of (250mg) and 2- in n,N-Dimethylformamide (10mL) exists Environment temperature stirs 72 hours.The mixture is quenched with water and is extracted into EtOAc, then with saturated sodium-chloride water solution into The washing of one step, is then washed with water.It by the drying of organic layer anhydrous sodium sulfate and is concentrated under reduced pressure, obtains reddish oil, be divided into Two parts.About 60mg is purified with preparative HPLC, obtains 2- [[6- amino -3,5- dicyano -4- (2,2,2- trifluoroethyl) - 2- pyridyl group] sulfanyl] -2- phenvl-acetamide (4.5mg) is cream solid.LCMS m/z=390 [M-H]–。1H NMR (300MHz, DMSO-d6) δ ppm 8.16 (br s, 1H), 7.85-7.66 (m, 1H), 7.65-7.59 (m, 2H), 7.41-7.27 (m, 5H), 5.57 (s, 1H), 3.78 (q, J=10.5Hz, 2H).
Remaining raw oil is ground, under reduced pressure filtering and with iso-hexane with isohexane, obtains 2- [[6- ammonia Base -3,5- dicyano -4- (2,2,2- trifluoroethyl) -2- pyridyl group] sulfanyl] -2- phenvl-acetamide (180mg), for palm fibre Color crystalline solid.
Step 2:2- ((3,5- dicyano -6- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base) -4- (2, 2,2- trifluoroethyl) pyridine -2- base) sulfenyl) -2- phenyl-acetamides
By 2- [[6- amino -3,5- dicyano -4- (2,2,2- trifluoroethyl) -2- pyridyl group] sulfanyl] -2- phenyl - Acetamide, the stirring suspension of (180mg, 0.46mmol) in anhydrous acetonitrile (10mL) with copper bromide (II) (175mg, It 0.78mmol) handles with nitrite tert-butyl (0.1mL, 0.8mmol), is then heated 20 minutes under 70 DEG C of nitrogen atmospheres.It will The mixture is cooled to environment temperature, is diluted with EtOAc (20mL) and is washed with salt water (10mL), then washed with water (10mL) It washs.It by the drying of organic layer anhydrous sodium sulfate and is concentrated under reduced pressure, obtains bottle green oil.With isohexane: ether (1:1, about 50mL) Stirring obtains solid precipitating.The mixture is filtered, is then concentrated in vacuo the solution, obtains green oil (54mg).To 48mg 2- (Isosorbide-5-Nitrae-diaza cycloheptyl is added in the oil and triethylamine (0.03mL, 0.23mmol) in the mixture in tetrahydrofuran (2mL) Alkane -1- base) ethyl alcohol (17mg, 0.12mmol).The mixture is stirred into 1h in environment temperature.By mixture EtOAc (20mL) dilution, is washed with water (3x 20mL), saturated sodium-chloride water solution (25mL), with anhydrous sodium sulfate drying and is depressurized dense Contracting.The residue is purified with preparative HPLC, obtains 2- [[3,5- dicyano -6- [4- (2- hydroxyethyl)-Isosorbide-5-Nitrae-diaza Cycloheptane -1- base] -4- (2,2,2- trifluoroethyl) -2- pyridyl group] sulfanyl] -2- phenvl-acetamide (5.7mg), for Huang The film of color.LCMS m/z=517.3 [M-H]–。1H NMR (300MHz, methanol-d4) δ ppm 7.62-7.33 (m, 5H), 5.50 (s, 1H), 4.21-3.99 (m, 4H), 3.95-3.80 (m, 4H), 3.45-3.35 (m, 2H), 3.30-3.14 (m, 2H), 3.07 (t, J=5.5Hz, 2H), 2.43-2.22 (m, 2H).
Embodiment 114
(2R) -2- ({ 3,5- dicyano -4- ethyl -6- [4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base] Pyridine -2- base } amino) -2- phenyl-acetamides
Step 1:(R) -2- ((the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) amino) -2- phenyl-acetamides
At 20 DEG C, chloro- 4- EthylPyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (is described into conjunction in embodiment 3, step 2 At agitating solution (R) -2- amino -2- phenyl-acetamides of 333mg, the 1.47mmol) in tetrahydrofuran (50mL) (446mg, 2.97mmol) is disposably handled.After 2 hours, which is diluted with EtOAc (100mL), with water (3x 100mL), saturated sodium-chloride water solution washs, and by the drying of Hydrophobic glass funnel and is concentrated under reduced pressure, obtains crude (R) -2- ((chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-) amino) -2- phenyl-acetamides (511mg), are white solid.LCMS M/z=338 [M-H]–。
Step 2:(R) -2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxyethyl) -1,4- Diazesuberane - 1- yl) pyridine -2- base) amino) -2- phenyl-acetamides
2- (Isosorbide-5-Nitrae-Diazesuberane -1- base) ethyl alcohol (44mg, 0.31mmol) is molten in tetrahydrofuran (3mL) Liquid (R) -2- ((chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-) amino) -2- phenyl-acetamides (48mg, 0.14mmol) It handles and is stirred at room temperature 1 hour.By the mixture loading to SiO2(1g) and with silica gel chromatography (4g RediSep column, With 0-25%, (methanol contains 5%NH3) CH2Cl2Elution), triturated under ether is then used, (R) -2- ((3,5- dicyano -4- are obtained Ethyl -6- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base) pyridine -2- base) amino) -2- phenyl-acetamides (56mg, 89% yield), is white solid.LCMS m/z=446 [M-H]–。1H NMR (300MHz, DMSO-d6)δppm 7.84 (s, 1H), 7.51-7.25 (m, 6H), 7.11 (br d, J=5.7Hz, 1H), 5.44 (d, J=6.0Hz, 1H), 4.52 (br S, 1H), 3.74 (br s, 4H), 3.50 (br s, 2H), 3.21-2.52 (m, 8H), 2.05-1.75 (m, 2H), 1.20 (t, J= 7.6Hz, 3H).
Embodiment 115
2- ({ 6- [(3S) -3- amino-pyrrolidine -1- base] -3,5- dicyano -4- cyclopropyl pyridine -2- base } sulfanyl) - 2- phenyl-acetamides
Step 1:(S)-(1- (the chloro- 3,5- dicyano -4- cyclopropyl pyridine -2- base of 6-) pyrrolidin-3-yl) carbamic acid The tert-butyl ester
In room temperature, (conjunction is described in embodiment 4, step 2 to chloro- 4- cyclopropyl pyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (S)-pyrrolidin-3-yl carbamic acid is added in the solution in n,N-Dimethylformamide (10mL) at 238mg, 1mmol) Then triethylamine (101mg, 1mmol) is added in the tert-butyl ester (186mg, 1mmol).The mixture is stirred at room temperature 1 hour, so It is diluted with water (50mL) and is extracted with EtOAc (50mL x 2) afterwards.It by combined organic layer drying and is concentrated in vacuo, obtains (S)- (1- (chloro- 3, the 5- dicyano -4- cyclopropyl pyridine -2- base of 6-) pyrrolidin-3-yl) t-butyl carbamate (300mg, 77%), It is brown oil.LCMS m/z=409.9 [M+Na]+。
Step 2:((3S) -1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl Yl pyridines -2- base) pyrrolidin-3-yl) t-butyl carbamate
By (S)-(1- (the chloro- 3,5- dicyano -4- cyclopropyl pyridine -2- base of 6-) pyrrolidin-3-yl) the tertiary fourth of carbamic acid The solution of ester (300mg, 0.77mmol) and KSAc (106mg, 0.92mmol) in n,N-Dimethylformamide (10mL) is in room Temperature stirring 30 minutes, then by methanesulfonic acid 2- amino -2- oxo -1- phenylethylester (212mg, 0.92mmol) and Et3N (155mg, 1.54mmol) adds to the solution.The mixture is stirred at room temperature 12 hours, is then used in combination with water (50mL) dilution EtOAc (50mL x 2) extraction.By combined organic layer anhydrous Na2SO4It is dry, it is concentrated in vacuo and pure by silica gel column chromatography Change (the DCM solution of 0-2%MeOH), obtains ((3S) -1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- bis- Cyano -4- cyclopropyl pyridine -2- base) pyrrolidin-3-yl) t-butyl carbamate (280mg, 70%) is white solid. LCMS m/z=518.8 [M+H]+。
Step 3:2- ({ 6- [(3S) -3- amino-pyrrolidine -1- base] -3,5- dicyano -4- cyclopropyl pyridine -2- base } sulphur Alkyl) -2- phenyl-acetamides
In room temperature, to ((3S) -1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ring PropyIpyridine -2- base) pyrrolidin-3-yl) t-butyl carbamate (280mg, 0.54mmol) is in the solution in DCM (6mL) It is added trifluoroacetic acid (3mL).The mixture is stirred at room temperature 12 hours, is then concentrated, water (50mL) is poured into, with saturation NaHCO3It basified (to pH=9) and is extracted with DCM (50mL x 2).Combined organic layer is dry, then concentration should Residue passes through silica gel chromatography (CH2Cl2: MeOH 20:1), obtain 2- ({ 6- [(3S) -3- amino-pyrrolidine -1- base] - 3,5- dicyano -4- cyclopropyl pyridine -2- bases } sulfanyl) -2- phenyl-acetamides (80mg, 36%) are white solid. LCMS m/z=418.9 [M+H]+。1H NMR (400MHz, DMSO) δ ppm 7.90 (br s, 1H), 7.55-7.47 (m, 2H), 7.43-7.25 (m, 4H), 5.58 (s, 1H), 4.01-3.70 (m, 3H), 3.65-3.44 (m, 3H), 2.16-1.92 (m, 3H), 1.80-1.65 (m, 1H), 1.17-1.08 (m, 2H), 0.96-0.90 (m, 2H).
Embodiment 116
2- ((3,5- dicyano -4- ethyl -6- (2,9- diaza spiro [5.5] hendecane -9- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides
To 2- [(the bromo- 3,5- dicyano -4- ethyl -2- pyridyl group of 6-) sulfanyl] -2- phenvl-acetamide (in embodiment 6, synthesis, 30mg, 0.07mmol are described in step 1) and 2,9- diaza spiro [5.5] hendecane -2- t-butyl formate hydrochloric acid Triethylamine (0.03mL, 0.22mmol) is added in salt (24mg, 0.08mmol) in the mixture in tetrahydrofuran (2mL).By institute It obtains mixture to stir 2 hours, is then diluted with EtOAc (20mL), washed with water (3x 20mL), then use saturated sodium chloride water Solution (25mL) washing, is filtered by Hydrophobic glass funnel and removes the solvent under reduced pressure.By the material loading to SiO2 (0.5g) and (4g RediSep column, uses the CH of 0-10%MeOH with silica gel chromatography2Cl2Solution is as eluant, eluent), it obtains Colorless oil.The oil is dissolved in CH2Cl2(2mL) and trifluoroacetic acid (0.5mL, 6.73mmol) is added.By the reaction mixture in room Temperature stirring 0.5 hour, which is removed and by the residue triturated under ether, is dried in vacuo at 50 DEG C.Pass through preparation Type HPLC is further purified, and obtains 2- [[3,5- dicyano -6- (2,9- diaza spiros [5.5] hendecane -9- base) -4- ethyl - 2- pyridyl group] sulfanyl] -2- phenvl-acetamide (13mg, 37% yield) is white solid.LCMS m/z=473 [M- H]–。1H NMR (300MHz, DMSO-d6) δ ppm 8.30 (s, 1H), 7.94 (s, 1H), 7.54-7.48 (m, 2H), 7.42-7.29 (m, 4H), 5.53 (s, 1H), 4.05-3.67 (m, 4H), 3.38 (br s, 2H), 2.78-2.71 (m, 4H), 1.61 (br s, 2H), 1.56-1.45 (m, 6H), 1.20 (t, J=7.6Hz, 3H).
Embodiment 117
2- ((3,5- dicyano -4- ethyl -6- (hexahydro -1H- pyrrolo- [1,2-a] [1,4] diaza cycloheptatriene base - 2 (3H)-yls) pyridine -2- base) sulfenyl) -2- phenyl-acetamides
To 2- [(the bromo- 3,5- dicyano -4- ethyl -2- pyridyl group of 6-) sulfanyl] -2- phenvl-acetamide (in embodiment 6, synthesis, 30mg, 0.07mmol are described in step 1) and 2,3,4,5,7,8,9,9a- octahydro -1H- pyrrolo-es [1,2-a] [1, 4] diazacyclo heptantriene (12mg, 0.08mmol) be added in the mixture in tetrahydrofuran (2mL) triethylamine (0.02mL, 0.16mmol) and by gained mixture stir 1 hour.Water (5mL) is added and continues stirring 30 minutes, then by the precipitating Filter is washed with water (3x 10mL) and is dried in vacuo at 50 DEG C, obtains 2- ((3,5- dicyano -4- ethyl -6- (hexahydro -1H- pyrroles Cough up simultaneously -2 (3H)-yl of [1,2-a] [1,4] diaza cycloheptatriene base) pyridine -2- base) sulfenyl) and -2- phenyl-acetamides it is non-right Isomer mixture (29mg, 84% yield) is reflected, is pale powder.LCMS m/z=459 [M-H]–。1H NMR (300MHz, DMSO-d6) δ ppm 7.99-7.86 (m, 1H), 7.48-7.25 (m, 6H), 5.50-5.40 (m, 1H), 4.72- 4.47 (m, 1H), 4.37-3.99 (m, 2H), 3.96-3.67 (m, 2H), 3.69-3.40 (m, 3H), 3.14-2.90 (m, 2H), 2.85-2.65 (m, 2H), 2.30-2.15 (m, 1H), 2.10 (br s, 2H), 2.02-1.60 (m, 2H), 1.20-1.13 (m, 3H)。
Embodiment 118
2- ((3,5- dicyano -4- ethyl -6- (2- methyl -2,9- diaza spiro [5.5] hendecane -9- base) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides
To 2- [(the bromo- 3,5- dicyano -4- ethyl -2- pyridyl group of 6-) sulfanyl] -2- phenvl-acetamide (in embodiment 6, synthesis, 30mg, 0.07mmol are described in step 1) and 2- methyl -2,9- diaza spiro [5.5] hendecane hydrochloride (17mg, 0.08mmol) triethylamine (0.03mL, 0.22mmol) is added in the mixture in tetrahydrofuran (2mL) and by gained Mixture stirs 18 hours.The mixture is diluted with EtOAc (20mL), is washed with water (3x 20mL), saturated sodium-chloride (25mL) It washs, filtered by Hydrophobic glass funnel and removes the solvent under reduced pressure.Raw product is purified with preparative HPLC, obtains 2- [[3,5- dicyano -4- ethyl -6- (2- methyl -2,9- diaza spiro [5.5] hendecane -9- base) -2- pyridyl group] sulfanyl] - The non-enantiomer mixture (15mg, 41% yield) of 2- phenvl-acetamide, is white powder.LCMS m/z=487.3 [M–H]–。1H NMR (300MHz, DMSO-d6) δ ppm 7.91 (s, 1H), 7.54-7.48 (m, 2H), 7.42-7.29 (m, 4H), 5.53 (s, 1H), 3.95-3.84 (m, 2H), 3.84-3.70 (m, 2H), 2.80-2.70 (m, 2H), 2.32-2.19 (m, 4H), 2.15 (s, 3H), 1.73-1.43 (m, 6H), 1.33 (br s, 2H), 1.20 (t, J=7.6Hz, 3H).
Embodiment 119
2- ((3,5- dicyano -6- (2- (Cvclopropvlmethvl) -2,9- diaza spiro [5.5] hendecane -9- base) -4- second Yl pyridines -2- base) sulfenyl) -2- phenylacetyl amine hydrochlorate
To 2- [(the bromo- 3,5- dicyano -4- ethyl -2- pyridyl group of 6-) sulfanyl] -2- phenvl-acetamide (in embodiment 6, synthesis, 27mg, 0.07mmol are described in step 1) and 2- (Cvclopropvlmethvl) -2,9- diaza spiro [5.5] hendecane two Triethylamine (0.04mL, 0.27mmol) is added in hydrochloride (21mg, 0.07mmol) in the mixture in tetrahydrofuran (2mL). The reaction mixture is stirred 18 hours, is then diluted with EtOAc (20mL), with water (3x 20mL), saturated sodium chloride solution (25mL) washing, is filtered by Hydrophobic glass funnel and removes the solvent under reduced pressure.By raw product preparative HPLC It purifies and gained residue is dissolved in DCM, filtered by Hydrophobic glass funnel and remove the solvent under reduced pressure.By subsequent residue It is dissolved in MeOH (2mL) and methanol HCl (3M, 0.4mL) is added.By the solvent remove and by required product triturated under ether and 50 DEG C of vacuum drying, obtain 2- [[3,5- dicyano -6- [2- (Cvclopropvlmethvl) -2,9- diaza spiro [5.5] hendecane -9- Base] -4- ethyl -2- pyridyl group] sulfanyl] -2- phenyl-acetyl amine hydrochlorate (18mg, 47% yield) is white powder. LCMS m/z=527.4 [M-H]–。1H NMR (300MHz, DMSO-d6) δ ppm 9.35 (br s, 1H), 7.96 (s, 1H), 7.55-7.49 (m, 2H), 7.47-7.27 (m, 4H), 5.54 (s, 1H), 4.06-3.88 (m, 2H), 3.88-3.71 (m, 2H), 3.60-3.43 (m, 2H), 3.17-3.01 (m, 1H), 2.93-2.71 (m, 5H), 2.06-1.74 (m, 6H), 1.48 (br s, 2H), 1.36-1.27 (m, 1H), 1.21 (t, J=7.6Hz, 3H), 0.66 (br d, J=7.8Hz, 2H), 0.54-0.30 (m, 2H)。
Embodiment 120
2- ((3,5- dicyano -6- (4- (3- (dimethylamino) propyl) piperazine -1- base) -4- ethylpyridine -2- base) Sulfenyl) -2- phenyl-acetamides
To 2- [(the bromo- 3,5- dicyano -4- ethyl -2- pyridyl group of 6-) sulfanyl] -2- phenvl-acetamide (in embodiment 6, synthesis, 30mg, 0.07mmol are described in step 1) and N, N- dimethyl -3- piperazine -1- base -propyl- 1- amine (15mg, Triethylamine (0.02mL, 0.16mmol) 0.09mmol) is added in the mixture in tetrahydrofuran (2mL) and mixes the reaction Object is stirred at room temperature 72 hours.The product mixtures are diluted with ethyl acetate (20mL), with water (3x 20mL), saturation chlorination Sodium (25mL) washing, is filtered by Hydrophobic glass funnel and removes the solvent under reduced pressure.By raw product silica gel chromatography (4g RediSep column, using the dichloromethane solution of 0-10% (methanol contains 5% ammonium hydroxide) as eluant, eluent), is then used The product of triturated under ether separation, is then dried in vacuo, obtains 2- ((3,5- dicyano -6- (4- (3- (dimethylamino) propyl) Piperazine -1- base) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides (20mg, 54% yield) are white solid. LCMS m/z=490.3 [M-H]-.1H NMR (300MHz, DMSO-d6) δ ppm 7.91 (s, 1H), 7.54-7.49 (m, 2H), 7.42-7.31 (m, 4H), 5.53 (s, 1H), 3.92-3.81 (m, 4H), 2.80-2.71 (m, 2H), 2.47-2.45 (m, 2H), 2.40-2.24 (m, 6H), 2.22 (s, 6H), 1.67-1.57 (m, 2H), 1.20 (t, J=7.5Hz, 3H).
Embodiment 121
2- ((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-3-yl) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；2,2,2- trifluoroacetic acid
To 2- [(the bromo- 3,5- dicyano -4- ethyl -2- pyridyl group of 6-) sulfanyl] -2- phenvl-acetamide (in embodiment 6, synthesis, 27mg, 0.07mmol are described in step 1) and 3- (4- piperidyl) pyrrolidines -1- t-butyl formate (19mg, Triethylamine (0.02mL, 0.15mmol) 0.07mmol) is added in the mixture in tetrahydrofuran (2mL).The reaction is mixed Object stirs 1 hour.The mixture is diluted with ethyl acetate (20mL), is washed with water (3x 20mL), saturated sodium-chloride (25mL) It washs, is filtered by Hydrophobic glass funnel, which is removed.By raw product silica gel chromatography (4g RediSep Column uses the dichloromethane solution of 0-10% methanol as eluant, eluent).Gained residue is dissolved in methylene chloride (2mL), is added Trifluoroacetic acid (0.5mL, 6.73mmol) simultaneously stirs subsequent mixture 0.5 hour in environment temperature.The solvent under reduced pressure is removed It goes and the product triturated under ether is obtained into 2- [[3,5- dicyano -4- ethyl -6- (4- pyrrolidines-in 50 DEG C of vacuum drying 3- base -1- piperidyl) -2- pyridyl group] sulfanyl] -2- phenvl-acetamide；2,2,2- trifluoroacetic acids (34mg, 86% yield), It is yellow solid.LCMS m/z=473.3 [M-H]-.1H NMR (300MHz, DMSO-d6) δ ppm 8.67 (br s, 2H), 7.92 (s, 1H), 7.55-7.49 (m, 2H), 7.43-7.30 (m, 4H), 5.53 (s, 1H), 4.69-4.47 (m, 2H), 3.42- 3.17 (m, 3H), 3.24-2.95 (m, 4H), 2.85-2.71 (m, 3H), 2.15-1.88 (m, 2H), 1.87-1.71 (m, 2H), 1.63-1.47 (m, 2H), 1.21 (t, J=7.6Hz, 3H).
Embodiment 122
2- ((6- ([4,4'- joins piperidines] -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；2,2,2- trifluoroacetic acid
To 2- [(the bromo- 3,5- dicyano -4- ethyl -2- pyridyl group of 6-) sulfanyl] -2- phenvl-acetamide (in embodiment 6, synthesis, 25mg, 0.06mmol are described in step 1) and 4- (4- piperidyl) piperidines -1- t-butyl formate (18mg, Triethylamine (0.02mL, 0.12mmol) 0.07mmol) is added in the mixture in tetrahydrofuran (2mL).By gained mixture Stirring 3 hours.The product mixtures are diluted with ethyl acetate (20mL), with water (3x 20mL), saturated sodium chloride solution (25mL) washing, is filtered by Hydrophobic glass funnel, which is removed.Raw product is dissolved in methylene chloride, is adsorbed In silica gel (0.5g) and with silica gel chromatography, (4g RediSep column uses the dichloromethane solution of 0-10% methanol as washing De- agent).The residue of recycling is dissolved in methylene chloride (2mL) and trifluoroacetic acid (0.5mL, 6.73mmol) is added.By the reaction It is stirred at room temperature 30 minutes and is concentrated.It is dried in vacuo by gained residue triturated under ether and at 50 DEG C, obtains 2- [[3,5- bis- Cyano -4- ethyl -6- [4- (4- piperidyl) -1- piperidyl] -2- pyridyl group] sulfanyl] -2- phenvl-acetamide；2,2,2- tri- Fluoroacetic acid (30mg, 80% yield), is white solid.LCMS:487.3 [M-H]–。1H NMR (300MHz, DMSO-d6)δppm 8.44 (br s, 1H), 8.25-8.04 (m, 1H), 7.92 (s, 1H), 7.57-7.47 (m, 2H), 7.45-7.27 (m, 4H), 5.54 (s, 1H), 4.73-4.53 (m, 2H), 3.30-3.22 (m, 2H), 3.21-2.97 (m, 2H), 2.88-2.68 (m, 4H), 1.90- 1.75 (m, 4H), 1.62-1.40 (m, 2H), 1.42-1.25 (m, 4H), 1.20 (t, J=7.6Hz, 3H).
Embodiment 123
2- ((6- (4- (2- amino-ethyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides
Step 1:(2- (4- benzyl diethylenediamine -1- base) ethyl) t-butyl carbamate
(2- bromoethyl) amino is added in the solution in acetonitrile (30mL) to 1- benzyl diethylenediamine (500mg, 2.84mmol) T-butyl formate (950mg, 4.26mmol) and K2CO3(784mg, 5.68mmol).The mixture is stirred 12 hours at 70 DEG C, Then it is concentrated in vacuo and passes through silica gel chromatography (DCM:MeOH 20:1), obtain (2- (4- benzyl diethylenediamine -1- base) ethyl) T-butyl carbamate (730mg, 81%), for oil.LCMS m/z=320.0 [M+H]+。
Step 2:(2- (4- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) piperazine -1- base) ethyl) carbamic acid The tert-butyl ester
To (2- (4- benzyl diethylenediamine -1- base) ethyl) t-butyl carbamate (730mg, 2.3mmol) at MeOH (20mL) In solution in be added Pd/C (73mg).The mixture is stirred overnight under room temperature nitrogen atmosphere.The mixture is filtered and incited somebody to action Filter vacuum concentration, obtains the residue of 400mg.In room temperature, to chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (in reality Example 3 is applied, synthesis, 393mg, 1.75mmol are described in step 2) on the solution in n,N-Dimethylformamide (15mL) is added State residue and Et3N(0.24mL 1.75mmol).The mixture is stirred at room temperature 5 minutes, is then diluted with water EtOAc extraction.By combined organic layer water and salt water washing, vacuum concentration passes through silica gel chromatography (petroleum ether: second Acetoacetic ester 40:60), obtain (2- (4- (chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-) piperazine -1- base) ethyl) amino first Tert-butyl acrylate (560mg, 77%).LCMS m/z=419.0 [M+H]+。
Step 3:(2- (4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperazine -1- base) ethyl) t-butyl carbamate
By (2- (4- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) piperazine -1- base) ethyl) tertiary fourth of carbamic acid The solution of ester (300mg, 0.72mmol) and KSAc (98mg, 0.86mmol) in n,N-Dimethylformamide (8mL) is in room temperature Stirring 30 minutes, then (describes conjunction for methanesulfonic acid 2- amino -2- oxo -1- phenylethylester in embodiment 3, step 5 At 197mg, 0.86mmol) and Et3N (0.2mL, 1.44mmol) adds to the solution.The mixture is stirred at room temperature overnight, Then it is diluted with water.The solid by filtration of precipitation is collected and is passed through silica gel chromatography (DCM:MeOH 20:1), is obtained (2- (4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperazine -1- Base) ethyl) t-butyl carbamate (210mg, 53%).LCMS m/z=549.8 [M+H]+。
Step 4:2- ((6- (4- (2- amino-ethyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides
In room temperature, to (2- (4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl Pyridine -2- base) piperazine -1- base) ethyl) solution addition of the t-butyl carbamate (210mg, 0.38mmol) in DCM (4mL) Trifluoroacetic acid (3mL).The mixture is stirred at room temperature overnight, is then concentrated in vacuo, in saturated water sodium bicarbonate aqueous solution It is extracted with and with DCM.Organic layer is washed with brine, be concentrated in vacuo and passes through silica gel chromatography (DCM:MeOH 5:1), Obtain 2- ((6- (4- (2- amino-ethyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide (135mg, 79%).LCMS m/z=449.8 [M+H]+。1H NMR (400MHz, CD3OD) δ ppm 7.57-7.53 (m, 2H), 7.45-7.37 (m, 3H), 5.50 (s, 1H), 4.06-3.96 (m, 4H), 3.12-3.06 (m, 2H), 2.92 (q, J= 7.6Hz, 2H), 2.70-2.62 (m, 6H), 1.32 (t, J=7.6Hz, 3H).4H is not observed.
Embodiment 124
2- ((6- (4- (3- aminopropyl) piperazine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) - 2- phenyl-acetamides
Step 1:4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine - 2- yl) piperazine -1- t-butyl formate
By 4- (chloro- 3, the 5- dicyano -4- cyclopropyl pyridine -2- base of 6-) piperazine -1- t-butyl formate (in embodiment 30, Synthesis, 1.2g, 3.1mmol are described in step 1) and thioacetic acid potassium (423mg, 3.71mmol) in n,N-Dimethylformamide Mixture in (25mL) is stirred at room temperature 30 minutes, then by methanesulfonic acid 2- amino -2- oxo -1- phenylethylester (in reality Example 3 is applied, synthesis, 850mg, 3.71mmol are described in step 5) and Et3N (939mg, 9.3mmol) adds to the reaction.This is mixed It closes object to be stirred at room temperature 12 hours, be subsequently poured into water (100mL) and extracted with EtOAc (100mL x2).By combined organic layer It is dried and concentrated.Remaining residue is passed through into silica gel chromatography (MeOH:CH2Cl21:80), 4- (6- ((2- ammonia is obtained Base -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine -2- base) piperazine -1- t-butyl formate (1.45g, 90%), is brown oil.LCMS m/z=518.9 [M+H]+。
Step 2:2- ((3,5- dicyano -4- cyclopropyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl second Amide
By 4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine -2- Base) mixture of piperazine -1- t-butyl formate (1.45g, 2.79mmol) and trifluoroacetic acid (2mL) in methylene chloride (6mL) It is stirred at room temperature 12 hours.After reaction mixture concentration, by remaining residue down in water (100mL), with saturation NaHCO3It is basified to be extracted to pH 9 and with DCM (100mL x 2).Combined organic layer is dried and concentrated, 2- is obtained ((3,5- dicyano -4- cyclopropyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides (1.0g, 85%), For white solid.LCMS m/z=419.0 [M+H]+。
Step 3:(3- (4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl Pyridine -2- base) piperazine -1- base) propyl) t-butyl carbamate
By 2- ((3,5- dicyano -4- cyclopropyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides (500mg, 1.19mmol), (3- bromopropyl) t-butyl carbamate (341mg, 1.43mmol), K2CO3(328mg, 2.38mmol) mixture in acetonitrile (10mL) stirs 12 hours at 70 DEG C.The reaction mixture is concentrated and will be remaining Residue passes through silica gel chromatography (CH2Cl2: methanol 30:1), obtain (3- (4- (6- ((2- amino -2- oxo -1- phenyl Ethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine -2- base) piperazine -1- base) propyl) t-butyl carbamate (200mg, 29% yield), it is brown oil.LCMS m/z=576.0 [M+H]+。
Step 4:2- ((6- (4- (3- aminopropyl) piperazine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) Sulfenyl) -2- phenyl-acetamides
By (3- (4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine - 2- yl) piperazine -1- base) propyl) t-butyl carbamate (200mg, 0.34mmol) and trifluoroacetic acid (1mL) be in methylene chloride Mixture in (5mL) is stirred at room temperature 12 hours.The reaction mixture is concentrated.By the residue down to water (50mL), lead to Addition saturated water sodium bicarbonate aqueous solution is crossed to be alkalized and use CH2Cl2(50mL x 2) extraction.Combined organic layer is dry And it is concentrated.Remaining residue is passed through into silica gel chromatography (CH2Cl2: methanol 30:1), obtain 2- ((6- (4- (3- amino Propyl) piperazine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) (80mg, 48% produces -2- phenyl-acetamides Rate), it is white solid.LCMS m/z=475.9 [M+H]+。1H NMR (400MHz, CD3OD) δ ppm 7.63-7.55 (m, 2H), 7.46-7.36 (m, 3H), 5.57 (s, 1H), 4.55-3.55 (m, 4H), 3.33-2.99 (m, 8H), 2.25-2.10 (m, 3H), 1.30-1.23 (m, 2H), 1.16-1.07 (m, 2H).4H is not observed.
Embodiment 125
2- ((3,5- dicyano -4- cyclopropyl -6- (4- ((4- methylpiperazine-1-yl) methyl) piperidin-1-yl) pyridine - 2- yl) sulfenyl) -2- phenyl-acetamides trifluoroacetate
The chloro- 4- cyclopropyl -6- of step 1:2- (4- ((4- methylpiperazine-1-yl) methyl) piperidin-1-yl) pyridine -3,5- Dimethoxy nitrile
By chloro- 4- cyclopropyl pyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (synthesis is described in embodiment 4, step 2, 500mg, 2.1mmol) and 1- methyl -4- (piperidin-4-ylmethyl) piperazine (500mg, 2.5mmol) be dissolved in methylene chloride (100mL) and triethylamine (250mg, 2.5mmol) is added.The reaction mixture is stirred 1 hour in environment temperature.By the mixing Object is washed with salt water (2x 100mL), dry with anhydrous sodium sulfate and be concentrated under reduced pressure, obtain title compound (700mg, 1.8mmol).LCMS m/z=398.8 [M+H]+.
Step 2:4- cyclopropyl -2- sulfydryl -6- (4- ((4- methylpiperazine-1-yl) methyl) piperidin-1-yl) pyridine -3, 5- dimethoxy nitrile
To the chloro- 4- cyclopropyl -6- of 2- (4- ((4- methylpiperazine-1-yl) methyl) piperidin-1-yl) pyridine -3,5- diformazan Nitrile (700mg, 1.8mmol) be added in the solution in n,N-Dimethylformamide (20mL) thioacetic acid potassium (208mg, 1.8mmol).The mixture is stirred 3 hours, is then diluted the mixture with ethyl acetate (200mL) and with salt water (2x It 100mL) washs, with anhydrous sodium sulfate drying and is concentrated under reduced pressure, obtains title compound (700mg, 1.8mmol).LCMS m/z =396.9 [M+H]+。
Step 3:2- ((3,5- dicyano -4- cyclopropyl -6- (4- ((4- methylpiperazine-1-yl) methyl) piperidin-1-yl) Pyridine -2- base) sulfenyl) -2- phenyl-acetamides trifluoroacetate
By 4- cyclopropyl -2- sulfydryl -6- (4- ((4- methylpiperazine-1-yl) methyl) piperidin-1-yl) pyridine -3,5- two Formonitrile HCN (700mg, 1.7mmol) is dissolved in n,N-Dimethylformamide (50mL), and methanesulfonic acid 2- amino -2- oxo -1- is then added Phenylethylester (synthesis, 500mg, 1.9mmol are described in embodiment 3, step 5) and potassium carbonate (300mg, 1.9mmol). The reaction mixture is stirred at room temperature overnight.Then the mixture is diluted with ethyl acetate (200mL), with salt water (2x It 100mL) washs, with sodium sulphate drying and is concentrated under reduced pressure.Residue preparative-HPLC is purified, title compound is obtained (200mg, 17.3%).LCMS m/z=529.8 [M+H]+。1H-NMR (400MHz, methanol-d4) δ ppm 7.54 (dd, J= 7.9,1.4Hz, 2H), 7.45-7.35 (m, 3H), 5.51 (s, 1H), 4.66 (t, J=14.1Hz, 2H), 3.41 (s, 4H), 3.18 (td, J=12.4,6.2Hz, 2H), 3.05 (s, 3H), 2.92 (s, 3H), 2.64 (d, J=7.1Hz, 2H), 2.16-1.92 (m, 4H), 1.43-1.29 (m, 3H), 1.28-1.21 (m, 2H), 1.14-1.03 (m, 2H).2H is not observed.
Embodiment 126
2- ((6- (4- Acetylpiperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide
By 2- [(the bromo- 3,5- dicyano -4- ethyl -2- pyridyl group of 6-) sulfanyl] -2- phenvl-acetamide (in embodiment 6, describe synthesis, 21mg, 0.05mmol in step 1) solution in tetrahydrofuran (2mL) with 1- Acetylpiperazine (20mg, It 0.16mmol) handles and is stirred 18 hours in environment temperature.The dry loading of the reaction mixture to silica gel (0.9g) and is used into silicon Glue chromatogram purification (4g RediSep column, with the CH of 0-5%MeOH2Cl2Solution elution), obtain 2- [[6- (4- Acetylpiperazine- 1- yl) -3,5- dicyano -4- ethyl -2- pyridyl group] sulfanyl] (22mg, 0.049mmol, 94% are produced -2- phenvl-acetamide Rate), it is white solid.LCMS m/z=449 [M+H]+。1H NMR (300MHz, DMSO-d6) δ ppm 7.91 (s, 1H), 7.55-7.30 (m, 6H), 5.54 (s, 1H), 4.05-3.79 (m, 4H), 3.67-3.53 (m, 4H), 2.78 (q, J=7.6Hz, 2H), 2.06 (s, 3H), 1.17 (t, J=7.3Hz, 3H).
Embodiment 127
2- ((3,5- dicyano -4- cyclopropyl -6- (dimethylamino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides
By 2- [(6- amino -3,5- dicyano -4- cyclopropyl -2- pyridyl group) sulfanyl] -2- phenvl-acetamide (in reality Example 51 is applied, synthesis, 200mg, 0.57mmol are described in step 2) the suspension bromine of stirring in anhydrous acetonitrile (10mL) Change copper (II) (217mg, 0.97mmol) and nitrite tert-butyl (0.12mL, 1mmol) processing, then under 70 DEG C of nitrogen atmospheres Heating 20 minutes.Then the reaction mixture is cooling, direct loading to silica gel (1.2g) and with silica gel chromatography (4g RediSep column, with the isohexane of 20-100%EtOAc), the crude light green solid of 92mg is obtained, is dropped It solves and unstable.By the solution dimethylamine solution of the crude solid (35mg) in tetrahydrofuran (4mL) and ethyl alcohol (1mL) It handles (methanol solution of 2M, 0.01mL, 0.21mmol) and is stirred 30 minutes in environment temperature.The product mixtures are being depressurized Lower concentration simultaneously purifies remaining residue with preparative HPLC, obtains 2- [[3,5- dicyano -4- cyclopropyl -6- (dimethyl Amino) -2- pyridyl group] sulfanyl] -2- phenvl-acetamide (7.2mg) is cream solid.LCMS m/z=376.1 [M- H]–。1H NMR (300MHz, DMSO-d6) δ ppm 7.90 (s, 1H), 7.55-7.47 (m, 2H), 7.47-7.22 (m, 4H), 5.58 (s, 1H), 3.31 (s, 6H), 2.28-1.95 (m, 1H), 1.24-0.87 (m, 4H).
Embodiment 128
2- (4- chlorphenyl) -2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) acetyl Amine
In environment temperature, to 2- (4- chlorphenyl) -2- hydroxy-acetic acid (250mg, 1.34mmol) in DCE (10mL) Thionyl chloride (0.29mL, 4.02mmol) is added in suspension and is heated to reflux the reaction mixture 1 hour.The product is mixed It closes object to be concentrated under reduced pressure, obtains the chloro- 2- of crude 2- (4- chlorphenyl) chloroacetic chloride (244mg), be cream solid, be not Purifying.In environment temperature, which is dissolved in Ammonia (10mL, 157.66mmol) and should Reaction mixture is heated to reflux, until HCl gas stops evolution.The product mixtures are concentrated under reduced pressure and are ground with ether Mill, obtains the chloro- 2- of 2- (4- chlorphenyl) acetamide (78mg), is cream solid, since its unstability does not obtain sufficiently Characterization.2- (dimethylamino) -4- ethyl -6- sulfanyl-pyridine -3,5- dimethoxy nitrile (is described in embodiment 92, step 3 Synthesis, 25mg, 0.11mmol) it is dissolved in n,N-Dimethylformamide (10mL), the chloro- 2- of 2- (4- chlorphenyl) acetyl is then added Then sodium bicarbonate (20mg, 0.24mmol) is added in amine (24mg, 0.12mmol).The reaction mixture is stirred in environment temperature It mixes 16 hours.The product mixtures are diluted with water and gained precipitating is washed with water under reduced pressure, is then washed, is obtained with ether To 2- (4- chlorphenyl) -2- [[3,5- dicyano -6- (dimethylamino) -4- ethyl -2- pyridyl group] sulfanyl] acetamide (13mg, 0.0325mmol) is cream solid.LCMS m/z=398.1 [M-H]–。1H NMR (300MHz, CDCl3)δppm 7.44-7.36 (m, 4H), 6.58 (br s, 1H), 5.48 (br s, 1H), 5.43 (s, 1H), 3.42 (s, 6H), 2.94 (q, J= 7.7Hz, 2H), 1.34 (t, J=7.6Hz, 3H).
Embodiment 129
2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxyethyl) piperazine -1- base) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides
By 2- [(the bromo- 3,5- dicyano -4- ethyl -2- pyridyl group of 6-) sulfanyl] -2- phenvl-acetamide (in embodiment 6, synthesis, 15mg, 0.04mmol are described in step 1) solution 1- (2- hydroxyethyl) piperazine in tetrahydrofuran (1mL) (0.012mL, 0.09mmol) processing is simultaneously stirred 18 hours in environment temperature.By the dry loading of the product mixtures to SiO2 (0.9g) and with silica gel chromatography (4g RediSep column, with 0-10%MeOH, 0-1%NH3/CH2Cl2Elution), obtain 2- [[3,5- dicyano -4- ethyl -6- [4- (2- hydroxyethyl) piperazine -1- base] -2- pyridyl group] sulfanyl] -2- phenyl-acetyl Amine (12mg, 0.0266mmol, 71% yield), is white solid.LCMS m/z=451 [M+H]+。1H NMR (300MHz, DMSO-d6) δ ppm 7.92 (s, 1H), 7.52 (d, J=6.7Hz, 2H), 7.45-7.28 (m, 4H), 5.53 (s, 1H), 4.59- 4.40 (m, 1H), 3.98-3.76 (m, 4H), 3.66-3.44 (m, 2H), 2.75 (q, J=7.5Hz, 2H), 2.48-2.40 (m, 6H), 1.20 (t, J=7.5Hz, 3H).
Embodiment 130
2- [(3,5- dicyano -4- cyclopropyl -6- morpholino -2- pyridyl group) sulfanyl] -2- phenvl-acetamide
By 2- [(6- amino -3,5- dicyano -4- cyclopropyl -2- pyridyl group) sulfanyl] -2- phenvl-acetamide (in reality Example 51 is applied, synthesis, 200mg, 0.57mmol are described in step 2) in the middle suspension bromination stirred of anhydrous acetonitrile (10mL) Copper (II) (217mg, 0.97mmol) and nitrite tert-butyl (0.12mL, 1mmol) processing, then add under 70 DEG C of nitrogen atmospheres Heat 20 minutes.Then the reaction mixture is cooling, direct loading to silica gel (1.2g) and with silica gel chromatography (4g RediSep column, with the isohexane of 20-100%EtOAc), the crude light green solid of 92mg is obtained, is dropped It solves and unstable.By the solution morpholine of the crude solid (50mg) in tetrahydrofuran (1mL) and ethyl alcohol (0.5mL) (0.03mL, 0.29mmol) processing is simultaneously stirred 30 minutes in environment temperature.The product mixtures are concentrated under reduced pressure and use system Standby type HPLC purifying (high pH), obtains 2- [(3,5- dicyano -4- cyclopropyl -6- morpholino -2- pyridyl group) sulfanyl] -2- benzene Base-acetamide (8.8mg, 0.0210mmol), is pale solid.LCMS m/z=418.1 [M-H]–。1H NMR (300MHz, DMSO-d6) δ ppm 7.88 (s, 1H), 7.64-7.47 (m, 2H), 7.44-7.20 (m, 4H), 5.51 (s, 1H), 3.93-3.81 (m, 4H), 3.74-3.66 (m, 4H), 2.15-2.07 (m, 1H), 1.17-1.10 (m, 2H), 1.01-0.94 (m, 2H)。
Embodiment 131
2- ((6- (4- benzoyl-piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl Acetamide
By 2- [(the bromo- 3,5- dicyano -4- ethyl -2- pyridyl group of 6-) sulfanyl] -2- phenvl-acetamide (in embodiment 6, synthesis, 15mg, 0.04mmol are described in step 1) solution N- benzoyl-piperazine in tetrahydrofuran (1mL) (17.78mg, 0.09mmol) processing is simultaneously stirred 18 hours in environment temperature.By the dry loading of the product mixtures to SiO2 (0.9g) and with silica gel chromatography (4g RediSep column, with 0-10%MeOH, 0-1%NH3/CH2Cl2Elution), then use second Ether grinding, obtain 2- [[6- (4- benzoyl-piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide (13mg, 0.0255mmol, 68% yield), is pale solid.LCMS m/z=509.1 [M-H]–。1H NMR (300MHz, DMSO-d6) δ ppm 7.87 (br s, 1H), 7.56-7.43 (m, 7H), 7.43-7.30 (m, 4H), 5.52 (s, 1H), 3.98 (br s, 4H), 3.77 (br s, 2H), 3.52 (br s, 2H), 2.78 (q, J=7.3Hz, 2H), 1.22 (t, J= 7.3Hz, 3H).
Embodiment 132
2- ((3,5- dicyano -4- ethyl -6- ((5S, 6S) -6- hydroxyl -1- (methyl sulphonyl) -1,8- diaza spiro [4.5] decyl- 8- yl) pyridine -2- base) sulfenyl) -2- phenyl-acetamides
To 2- [(the bromo- 3,5- dicyano -4- ethyl -2- pyridyl group of 6-) sulfanyl] -2- phenvl-acetamide (in embodiment 6, synthesis, 27mg, 0.07mmol are described in step 1) and (5S, 6S) -1- methyl sulphonyl -1,8- diaza spiro [4.5] decyl- Triethylamine (0.02mL, 0.15mmol) is added in 6- alcohol (17.34mg, 0.07mmol) in the mixture in tetrahydrofuran (2mL). The reaction mixture is stirred 72 hours.The mixture is diluted with EtOAc (20mL), with water (3x 20mL), salt water (25mL) Washing, is filtered by Hydrophobic glass funnel and removes the solvent under reduced pressure.The residue is dissolved in DMSO and uses preparative HPLC Purifying, obtains 2- ((3,5- dicyano -4- ethyl -6- ((5S, 6S) -6- hydroxyl -1- (methyl sulphonyl) -1,8- diaza spiro [4.5] decyl- 8- yl) pyridine -2- base) sulfenyl) -2- phenyl-acetamides (4mg, 11% yield) are white powder.LCMS m/z =533.3 [M-H]–。1H NMR (300MHz, CDCl3) δ ppm 7.55-7.30 (m, 6H), 7.07 (br s, 1H), 5.80 (br S, 1H), 5.30 (s, 1H), 4.81 (dd, J=4.5,10.8Hz, 1H), 4.45-4.32 (m, 1H), 4.23-4.08 (m, 1H), 4.08-3.83 (m, 1H), 3.70-3.52 (m, 1H), 3.45-3.26 (m, 2H), 3.05 (s, 3H), 3.01-2.91 (m, 2H), 2.91-2.78 (m, 1H), 2.56-2.21 (m, 2H), 2.07-1.70 (m, 3H), 1.37 (t, J=7.6Hz, 3H).
Embodiment 133
2- ((3,5- dicyano -6- (4,4- difluoropiperdin -1- base) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide
To 2- [(the bromo- 3,5- dicyano -4- ethyl -2- pyridyl group of 6-) sulfanyl] -2- phenvl-acetamide (in embodiment 6, synthesis, 30mg, 0.070mmol are described in step 1) 4,4- difluoro piperazine is added in the mixture in tetrahydrofuran (2mL) Then triethylamine (0.023mL, 0.16mmol) is added in thiamine hydrochloride (13mg, 0.08mmol).The reaction mixture is stirred 17 Hour.The reaction mixture is diluted with ethyl acetate (20mL), with water (3x 20mL), saturated sodium-chloride water solution (25mL) Washing, is filtered by Hydrophobic glass funnel and removes the solvent under reduced pressure.Obtained solid triturated under ether is simultaneously dry in 50 DEG C of vacuum It is dry, obtain 2- [[3,5- dicyano -6- (4,4- bis- fluoro- 1- piperidyl) -4- ethyl -2- pyridyl group] sulfanyl] -2- phenyl-second Amide (22mg, 67%), is yellow solid.LCMS m/z=440.2 [M-H]–。1H NMR (300MHz, DMSO-d6)δppm 7.91 (s, 1H), 7.59-7.47 (m, 2H), 7.46-7.30 (m, 4H), 5.53 (s, 1H), 3.96 (br t, J=5.5Hz, 4H), 2.86-2.70 (m, 2H), 2.29-2.03 (m, 4H), 1.22 (t, J=7.6Hz, 3H).
Embodiment 134
(R) -2- ((3,5- dicyano -4- ethyl -6- ((R) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides
Step 1:(R) the chloro- 4- ethyl -6- of -2- (3- hydroxyl pyrrolidine -1- base) pyridine -3,5- dimethoxy nitrile
To chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in embodiment 3, step 2,600mg, 2.65mmol) and (R)-pyrrolidines -3- alcohol (231mg, 2.65mmol) is in the solution in n,N-Dimethylformamide (15mL) It is added triethylamine (0.370mL, 2.65mmol).The reaction mixture is stirred at room temperature 30 minutes.The mixture is poured into water It is extracted in (100mL) and with ethyl acetate (100mL x 2).Combined organic layer is dried and concentrated, the chloro- 4- of (R) -2- is obtained Ethyl -6- (3- hydroxyl pyrrolidine -1- base) pyridine -3,5- dimethoxy nitrile (560mg, 76% yield), is pale solid.LCMS M/z=277.0 [M+H]+。
Step 2:2- ((3,5- dicyano -4- ethyl -6- ((R) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides
In room temperature, by the chloro- 4- ethyl -6- of (R) -2- (3- hydroxyl pyrrolidine -1- base) pyridine -3,5- dimethoxy nitrile (500mg, 1.81mmol) and the solution of thioacetic acid potassium (248mg, 2.17mmol) in n,N-Dimethylformamide (15mL) stirs 30 points Clock, then by methanesulfonic acid 2- amino -2- oxo -1- phenylethylester (describe synthesis in embodiment 3, step 5,497mg, 2.17mmol) and triethylamine (0.504mL, 3.61mmol) adds to the solution.The mixture is stirred at room temperature 12 hours, then It pours into water (50mL) and is extracted with ethyl acetate (50mL x 2).Combined organic layer is dry, it is concentrated and by remaining remnants Object obtains 2- ((3,5- dicyano -4- ethyl -6- ((R) -3- hydroxyl pyrroles by silica gel chromatography (MeOH:DCM 1:50) Cough up alkane -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides (400mg, 54%) are white solid.LCMS m/z= 408.0[M+H]+。
Step 3:(R) -2- ((3,5- dicyano -4- ethyl -6- ((R) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides
By 2- ((3,5- dicyano -4- ethyl -6- ((R) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides (300mg, 0.736mmol) separate (column chiralpak-IB, eluent hexane-by chiral preparative-HPLC EtOH (containing diethylamine)), obtain (R) -2- ((3,5- dicyano -4- ethyl -6- ((R) -3- hydroxyl pyrrolidine -1- base) pyridine - 2- yl) sulfenyl) -2- phenyl-acetamides (80mg).LCMS m/z=408.1 [M+H]+。1H NMR (400MHz, DMSO-d6)δppm 7.92 (br s, 1H), 7.53 (br s, 1H), 7.52-7.49 (m, 1H), 7.44-7.23 (m, 4H), 5.61 (s, 1H), 5.15 (s, 1H), 4.41 (s, 1H), 4.01-3.66 (m, 4H), 2.74 (q, J=7.5Hz, 2H), 2.05-1.86 (m, 2H), 1.21 (q, J=7.4Hz, 3H).
Embodiment 135
2- ((3,5- dicyano -4- (furans -2- base) -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides
Step 1:3,5- dicyano -4- (furans -2- base) -6- pyridone -2- methanol ammonium hydroxide
To furans -2- formaldehyde (13.9g, 145mmol) and 2- cyanoacetamide (12.16g, 145mmol) in water Ammonium hydroxide (7.99mL, 25%, aqueous solution) is added in solution in (150mL).The reaction is stirred at room temperature 18 hours.It will The mixture filters and washs filter cake with cold methanol.It dries solid methanol trituration and in an oven, obtains 3,5- Dicyano -4- (furans -2- base) -6- pyridone -2- methanol ammonium hydroxide (13g, crude), is faint yellow solid.LCMS m/z= 226.1[M]–.
The chloro- 4- of step 2:2,6- bis- (furans -2- base) pyridine -3,5- dimethoxy nitrile
In sealed tube, by 3,5- dicyano -4- (furans -2- base) -6- pyridone -2- methanol ammonium hydroxide (9g, 36.8mmol) it is added slowly to POCl3(90mL).The mixture is stirred overnight at 150 DEG C.The solvent under reduced pressure removes.This is residual Excess is down to ice water.The solid by filtration is collected, drying simultaneously (is washed by silica gel chromatography with DCM- hexane 0-10% It is de-), the chloro- 4- of 2,6- bis- (furans -2- base) pyridine -3,5- dimethoxy nitrile (500mg, 5%) is obtained, is light yellow solid.1H NMR (400MHz, CDCl3) δ ppm 7.90-7.88 (m, 2H), 6.79 (dd, J=3.7,1.7Hz, 1H).
Step 3:2- ((3,5- dicyano -4- (furans -2- base) -6- (4- methyl-1,4- Diazesuberane -1- base) Pyridine -2- base) sulfenyl) -2- phenyl-acetamides
To the chloro- 4- of 2,6- bis- (furans -2- base) pyridine -3,5- dimethoxy nitrile (200mg, 0.76mmol) in N, N- dimethyl 1- methyl-1 is added in solution in formamide (10mL), three second are then added dropwise in 4- Diazesuberane (82mg, 0.72mmol) Amine (0.105mL, 0.76mmol).The reaction is stirred at room temperature 1 hour.KSAc (104mg, 0.91mmol) is added into the mixing Object.The reaction is stirred at room temperature 30 minutes, then by methanesulfonic acid 2- amino -2- oxo -1- phenylethylester (in embodiment 3, Synthesis, 208mg, 0.91mmol are described in step 5) and triethylamine (0.21mL, 1.52mmol) add to the solution.By the mixing Object is stirred at room temperature overnight, and is then concentrated in vacuo and is used in combination by silica gel chromatography (being eluted with MeOH-DCM 0-10%) Triturated under ether obtains 2- { [3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base] sulfanyl } -2- phenylacetyl Amine (26mg, 7.12%), is faint yellow solid.LCMS m/z=473.3 [M+H]+。1H NMR (400MHz, CDCl3)δppm (7.72 s, 1H), 7.48-7.35 (m, 6H), 6.65 (s, 2H), 5.63 (br s, 1H), 5.39 (s, 1H), 4.15-3.82 (m, 4H), 3.01-2.83 (m, 2H), 2.79-2.58 (m, 2H), 2.46 (s, 3H), 2.25-2.07 (m, 2H).
Embodiment 136:
2- ((6- (4- amino -4- methyl piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide
Step 1:(1- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) -4- methyl piperidine -4- base) carbamic acid The tert-butyl ester
To chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in embodiment 3, step 2,316mg, 1.400mmol) solution in methylene chloride (30mL) be added (4- methyl piperidine -4- base) t-butyl carbamate (300mg, 1.400mmol) and triethylamine (142mg 1.400mmol).The mixture is stirred at room temperature 12 hours.The mixture is used DCM (50mL) dilution, it is dry with water and salt water washing, it is concentrated to get (1- (chloro- 3, the 5- dicyano -4- ethylpyridine -2- of 6- Base) -4- methyl piperidine -4- base) t-butyl carbamate (320mg, 57% yield) is brown oil.LCMS m/z=426.0 [M+Na]+。
Step 2:(1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) -4- methyl piperidine -4- base) t-butyl carbamate
To (1- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) -4- methyl piperidine -4- base) the tertiary fourth of carbamic acid Thioacetic acid potassium (136mg, 1.188mmol) is added in ester (320mg, 0.792mmol) in the solution in DMF (4mL).This is mixed Conjunction object is stirred at room temperature 1 hour and reaction similar with progress merges, and uses (1- (the 6- chloro- 3,5- of 123mg (0.305mmol) Dicyano -4- ethylpyridine -2- base) -4- methyl piperidine -4- base) t-butyl carbamate is as starting material.To the anti-of merging Answer middle addition potassium carbonate (303mg, 2.192mmol).The mixture is stirred at room temperature 1 hour and methanesulfonic acid 2- amino-is added 2- oxo -1- phenylethylester (synthesis, 377mg, 1.644mmol are described in embodiment 3, step 5).The mixture is existed It is stirred at room temperature 12 hours.The mixture is diluted with water (60mL) and is extracted with ethyl acetate (30mL x 3).By the organic phase With water and salt water washing, drying, concentration and in silica gel column purification (petrol ether/ethyl acetate=1/1), (1- (6- ((2- ammonia is obtained Base -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) -4- methyl piperidine -4- base) amino first Tert-butyl acrylate (540mg, 1.010mmol).LCMS m/z=535.2 [M+H]+。
Step 3:2- ((6- (4- amino -4- methyl piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides
By (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) -4- methyl piperidine -4- base) t-butyl carbamate (230mg, 0.430mmol) adds to trifluoroacetic acid (1mL) in dichloromethane Solution in alkane (10mL).The solution is stirred at room temperature 6 hours.PH is adjusted to 7-8.The mixture is concentrated, then will The residue is purified with preparative-HPLC, obtains product 2- ((6- (4- amino -4- methyl piperidine -1- base) -3,5- dicyan Base -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides (130mg, 70% yield) are white solid.LCMS m/z= 435.1[M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.93 (s, 3H), 7.52 (d, J=7.0Hz, 2H), 7.44- 7.31 (m, 4H), 5.53 (s, 1H), 4.36-4.09 (m, 2H), 3.79-3.61 (m, 2H), 2.78 (q, J=7.4Hz, 2H), 1.86-1.71 (m, 4H), 1.39 (s, 3H), 1.22 (t, J=7.6Hz, 3H).
Embodiment 137:
2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) acetamide, trifluoroacetate
Step 1:(2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) amino) -2- oxoethyl) t-butyl carbamate
By chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in 3 step 2 of embodiment, 1.212g, 5.36mmol), (2- oxo -2- (piperidin-4-yl amino) ethyl) t-butyl carbamate (1.38g, 5.36mmol) He Sanyi Mixture of the amine (1.085g, 10.73mmol) in methylene chloride (30mL) is stirred at room temperature overnight, and is then concentrated in vacuo.It will The residue purifies on a silica gel column, is eluted with hexane/EtOAc (1/1), obtains the residue of 1.5g.To the residue (0.9g) thioacetic acid potassium (0.276g, 2.416mmol) is added in the solution in n,N-Dimethylformamide (15mL) and will The mixture is stirred at room temperature overnight, and then uses K2CO3(0.557g, 4.03mmol) is in room temperature processing.By gained mixture in room Temperature stirring 1 hour, is then handled with methanesulfonic acid 2- amino -2- oxo -1- phenylethylester and (is described in 3 step 5 of embodiment Synthesis, 0.699g, 3.02mmol).Gained mixture is stirred at room temperature overnight, then diluted with EtOAc and uses water and salt water Washing.By organic phase Na2SO4It dries and is concentrated in vacuo, the residue is ground with EtOAc/ hexane (1/1) then, is obtained (2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidines -4- Base) amino) -2- oxoethyl) t-butyl carbamate (0.6g).LCMS m/z=578.3 [M+H]+。
Step 3:2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- Ethylpyridine -2- base) piperidin-4-yl) acetamide 2,2,2- trifluoroacetate
At 0 DEG C, to (2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl Pyridine -2- base) piperidin-4-yl) amino) -2- oxoethyl) t-butyl carbamate (0.55g) is in methylene chloride (10mL) Solution in 2,2,2- trifluoroacetic acids (868mg, 7.62mmol) are added.Gained mixture is stirred at room temperature 2 hours, then very Then residue preparative-HPLC is purified and (is eluted with Me-CN/TFA 0.1%), obtains 2- amino-N- by sky concentration (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl) Acetamide 2,2,2- trifluoroacetate (120mg).LCMS m/z=478.1 [M+H]+.1H NMR (400MHz, DMSO-d6)δppm 8.43 (d, J=7.4Hz, 1H), 8.03 (s, 2H), 7.95 (s, 1H), 7.52 (d, J=7.0Hz, 2H), 7.43-7.31 (m, 4H), 5.54 (s, 1H), 4.42 (m, 2H), 4.00 (m, 1H), 3.56 (q, J=5.6Hz, 2H), 3.41 (t, J=12.4Hz, 2H), 2.77 (m, 2H), 1.94 (d, J=10.4Hz, 2H), 1.57-1.41 (m, 2H), 1.21 (t, J=7.6Hz, 3H).
Embodiment 138:
(2S) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- second Yl pyridines -2- base) piperidin-4-yl) propionamide, trifluoroacetate
Step 1:4- (2- (t-butoxycarbonyl amino) acetylamino) piperidines -1- benzyl formate
By 4- amino piperidine -1- benzyl formate (6.4g, 27.3mmol), (S) -2- ((tertbutyloxycarbonyl) amino) propionic acid (5.17g, 27.3mmol), 1H- benzo [d] [1,2,3] triazole -4- alcohol (4.43g, 32.8mmol), N1- ((ethylimino) Methylene)-N3, N3- dimethyl propylene -1,3- diamines (5.09g, 32.8mmol) and 4- methyl morpholine (5.53g, 54.6mmol) exist Mixture in n,N-Dimethylformamide (30mL) is stirred at room temperature overnight, and is then concentrated in vacuo.By residue EtOAc Dilute and use 1N HCL aqueous solution, saturation NaHCO3Solution and salt water washing.The organic phase is dense with the dry simultaneously vacuum of sodium sulphate Contracting.By the residue silica gel chromatography, is eluted with hexane/EtOAc, obtain (S) -4- (2- ((tertbutyloxycarbonyl) amino) Propionamido-) piperidines -1- benzyl formate (8.6g, 58% yield).LCMS m/z=428.1 [M+Na]+。
Step 2:(S) -1- oxo -1- (piperidin-4-yl amino) propyl- 2- carbamate
In room temperature, to (S) -4- (2- ((tertbutyloxycarbonyl) amino) propionamido-) piperidines -1- benzyl formate (2.34g, 10%Pd/C (0.7g) 5.77mmol) is added in the solution in methanol (50mL).By the mixture in room temperature H2Under it is stirred Then night is filtered and concentrated in vacuo, obtain crude (S)-(1- oxo -1- (piperidin-4-yl amino) propyl- 2- yl) carbamic acid The tert-butyl ester (1.56g).LCMS m/z=272.2 [M+H]+。
Step 3:(S) -1- (1- (6- (2- amino -2- oxo -1- phenylethyl sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl amino) -1- oxo propyl- 2- carbamate
By chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in 3 step 2 of embodiment, 1.300g, 5.75mmol), (S)-(1- oxo -1- (piperidin-4-yl amino) propyl- 2- yl) t-butyl carbamate (1.56g, 5.75mmol) It is stirred at room temperature overnight with mixture of the triethylamine (1.163g, 11.50mmol) in methylene chloride (30mL), then vacuum is dense Contracting, by the residue silica gel chromatography, affords (S)-(1- ((1- (chloro- 3,5- bis- of 6- with hexane/EtOAc (1/1) Cyano -4- ethylpyridine -2- base) piperidin-4-yl) amino) -1- oxo propyl- 2- yl) t-butyl carbamate (1.8g, 3.90mmol, 68% yield).To (S)-(1- ((1- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) piperidin-4-yl) ammonia Base) -1- oxo propyl- 2- yl) t-butyl carbamate (920mg, 1.996mmol) is in n,N-Dimethylformamide (15mL) Thioacetic acid potassium (274mg, 2.395mmol) is added in solution and is stirred at room temperature overnight the mixture, is then used in room temperature K2CO3(552mg, 3.99mmol) processing.Gained mixture is stirred at room temperature 1 hour, methanesulfonic acid 2- amino -2- oxygen is then used Generation -1- phenylethylester processing (describing synthesis, 692mg, 2.99mmol in 3 step 5 of embodiment).Gained mixture is existed It is stirred overnight at room temperature, water and salt water washing is then diluted and used with EtOAc.By organic phase Na2SO4It dries and is concentrated in vacuo. The residue is ground with EtOAc/ hexane (1/1), obtains ((2S) -1- ((1- (6- ((2- amino -2- oxo -1- phenyl second Base) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl) amino) -1- oxo propyl- 2- yl) carbamic acid uncle Butyl ester (0.7g).LCMS m/z=592.3 [M+H]+。
Step 4:(2S) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyan Base -4- ethylpyridine -2- base) piperidin-4-yl) propionamide, trifluoroacetate
At 0 DEG C, to ((2S) -1- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano - 4- ethylpyridine -2- base) piperidin-4-yl) amino) -1- oxo propyl- 2- yl) t-butyl carbamate (0.65g, 1.098mmol) 2,2,2- trifluoroacetic acids (1.253g, 10.98mmol) are added in the solution in methylene chloride (10mL).By the mixture in room Temperature stirring 2 hours, is then concentrated in vacuo.The residue is purified and (is eluted with Me-CN/TFA0.1%) with preparative-HPLC column, Obtain (2S) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) propionamide, trifluoroacetate (110mg, 17% yield).LCMS m/z=492.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.44 (d, J=7.2Hz, 1H), 8.13 (s, 2H), 7.96 (s, 1H), 7.53 (d, J= 7.1Hz, 2H), 7.45-7.28 (m, 4H), 5.55 (s, 1H), 4.44 (t, J=11.2Hz, 2H), 3.98 (m, 1H), 3.89- 3.76 (m, 1H), 3.40 (m, 2H), 2.77 (q, J=7.5Hz, 2H), 1.93 (m, 2H), 1.50 (m, 2H), 1.36 (d, J= 6.9Hz, 3H), 1.21 (t, J=7.6Hz, 3H).
Embodiment 139:
2- ((6- (4- (3- amino oxetanyl -3- carbonyl) piperazine -1- base) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) sulfenyl) -2- phenyl-acetamides, formates
Step 1:3- ((tertbutyloxycarbonyl) amino) oxetanyl -3- formic acid
By 3- amino oxetanyl -3- formic acid (800mg, 6.83mmol), tetramethylammonium hydroxide (507mg, 5.56mmol), mixture of the di-tert-butyl dicarbonate (1640mg, 7.51mmol) in acetonitrile (30mL) is small in 50 DEG C of stirrings 12 When.The mixture is concentrated, then by the residue flash column chromatography, obtains 3- ((tertbutyloxycarbonyl) amino) oxa- Cyclobutane base -3- formic acid (1.3g, 88% yield).LCMS m/z=218.1 [M+H]+。
Step 2:(3- (4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperazine -1- carbonyl) oxetanyl -3- base) t-butyl carbamate
By 3- ((tertbutyloxycarbonyl) amino) oxetanyl -3- formic acid (120mg, 0.552mmol), 2- ((3,5- Dicyano -4- ethyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides (describe conjunction in embodiment 55 At 247mg, 0.608mmol), N- ((ethylimino) methylene)-N, N- dimethyl propylene -1,3- diamines (103mg, It 0.663mmol) is added in N,N-dimethylformamide (10mL) and is stirred 4 hours at 30 DEG C.Then water (30mL) is added and incites somebody to action The mixture is extracted with ethyl acetate (30mL x 3).The organic phase is dry with sodium sulphate, it is concentrated and pure with flash column chromatography Change, obtains (3- (4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) Piperazine -1- carbonyl) oxetanyl -3- base) t-butyl carbamate (230mg, 69% yield).LCMS m/z=628.2 [M+Na]+。
Step 3:2- ((6- (4- (3- amino oxetanyl -3- carbonyl) piperazine -1- base) -3,5- dicyano -4- second Yl pyridines -2- base) sulfenyl) -2- phenyl-acetamides, formates
By (3- (4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) piperazine -1- carbonyl) oxetanyl -3- base) t-butyl carbamate (230mg, 0.380mmol) addition methylene chloride In (20mL), 2,2,2- trifluoroacetic acids (3mL, 39.5mmol) are then added.By the mixture 25 DEG C stir 3 hours, then It is washed with water (30mL x 2).The organic phase is dry with sodium sulphate, it is concentrated and is purified with preparative-HPLC, obtain 2- ((6- (4- (3- amino oxetanyl -3- carbonyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides, formates (100mg, 48% yield).LCMS m/z=506.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.44 (s, 1H), 7.95 (s, 1H), 7.52 (d, J=7.1Hz, 2H), 7.43-7.32 (m, 3H), 5.55 (s, 1H), 4.90 (d, J=6.1Hz, 2H), 4.41 (d, J=6.1Hz, 2H), 4.00-3.85 (m, 4H), 3.64-3.58 (m, 2H), 3.49- 3.44 (m, 2H), 2.78 (q, J=7.5Hz, 2H), 1.22 (t, J=7.6Hz, 3H).
Embodiment 140
4- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) tetrahydro -2H- pyrans -4- formamide, trifluoroacetate
To 2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide (synthesis, 1g, 2.378mmol are described in embodiment 143, step 2) adds in the solution in methylene chloride (50mL) Enter HATU (0.904g, 2.378mmol), triethylamine (0.241g, 2.378mmol) and 4- ((tertbutyloxycarbonyl) amino) tetrahydro- 2H- pyrans -4- formic acid (0.583g, 2.378mmol).The mixture is stirred overnight at 25 DEG C.Then it is dense under reduced pressure Contracting, then purifies the residue on a silica gel column, it is eluted with hexane/EtOAc.Gained Boc derivative is dissolved in DCM (20mL) and TFA (2g) is added.The mixture is stirred at room temperature overnight.The reaction mixture is concentrated, then by the remnants Object is purified with preparative-HPLC, obtains 4- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- Dicyano -4- ethylpyridine -2- base) piperidin-4-yl) tetrahydro -2H- pyrans -4- formamide, trifluoroacetate (120mg, 0.181mmol, 8% yield).LCMS m/z=548 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm8.42 (s, 3H), 8.28 (d, J=7.6Hz, 1H), 7.94 (s, 1H), 7.53 (d, J=7.0Hz, 2H), 7.43-7.32 (m, 4H), 5.54 (s, 1H), 4.53 (t, J=14.9Hz, 2H), 4.05 (s, 1H), 3.73 (s, 4H), 3.33 (dd, J=11.5,6.3Hz, 2H), 2.77 (q, J=7.4Hz, 2H), 2.33-2.20 (m, 2H), 1.89 (d, J=13.5Hz, 2H), 1.68 (d, J=13.0Hz, 2H), 1.62-1.47 (m, 2H), 1.22 (t, J=7.6Hz, 3H).
Embodiment 141
2- ((6- (4- (4- amino tetrahydro -2H- pyrans -4- carbonyl) piperazine -1- base) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) sulfenyl) -2- phenyl-acetamides, trifluoroacetate
To 2- ((3,5- dicyano -4- ethyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides ( Synthesis, 800mg, 1.968mmol are described in embodiment 55) HATU is added in the solution in methylene chloride (50mL) (748mg, 1.968mmol), triethylamine (199mg, 1.968mmol) and 4- ((tertbutyloxycarbonyl) amino) tetrahydro -2H- pyrans - 4- formic acid (483mg, 1.968mmol).The mixture is stirred overnight at 25 DEG C, is concentrated under reduced pressure, then loads the residue To silicagel column, it is eluted with hexane/EtOAc, obtains the Boc derivative.By the Boc derivative be dissolved in DCM (5mL) and It is stirred at room temperature overnight in TFA (2g) and by the mixture.The reaction mixture is concentrated and preparative-HPLC is used to purify, is obtained To 2- ((6- (4- (4- amino tetrahydro -2H- pyrans -4- carbonyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) Sulfenyl) -2- phenyl-acetamides, trifluoroacetate (120mg, 9% yield).LCMS m/z=534 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.53 (s, 3H), 7.97 (s, 1H), 7.53 (d, J=7.0Hz, 2H), 7.46-7.31 (m, 4H), 5.57 (s, 1H), 4.01 (s, 4H), 3.94-3.65 (m, 8H), 2.79 (q, J=7.5Hz, 2H), 2.35 (m, 2H), 1.77 (d, J=14.6Hz, 2H), 1.23 (t, J=7.6Hz, 3H).
Embodiment 142
2- ((3,5- dicyano -6- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base) -4- methoxyl group pyrrole Pyridine -2- base) sulfenyl) -2- phenyl-acetamides
Step 1:(2- (dimethoxymethylene) malononitrile)
By ethylene -1,1,2,2- tetra- formonitrile HCNs (10.23g, 80mmol), urea (1.439g, 23.96mmol) and methanol The reaction mixture of (30.7ml, 759mmol) stirs 50 minutes.Ether (150mL) is added in the reaction mixture, it is then cold But it to -78 DEG C, while stirring 60 minutes.The solid is filtered and is washed with cold ether/hexane, obtaining 2-, (dimethoxy is sub- Methyl) malononitrile (8.35g, 60.5mmol, 76% yield) is faint yellow solid.LCMS m/z=138.9 [M+H]+。
Step 2:2- amino -6- chloro-4-methoxy pyridine -3,5- dimethoxy nitrile
By malononitrile (0.488g, 7.38mmol) and potassium tert-butoxide (0.870g, 7.60mmol) in methanol (15mL) Reaction mixture stirs 30 minutes at 50 DEG C, then by 2- (dimethoxymethylene) malononitrile (1g, 7.24mmol) in methanol Solution in (15mL) is added slowly in the mixture.The reaction mixture is reheated 100 minutes at 50 DEG C.The solvent is subtracted Pressure removes, and acetone (20mL) and dense HCl (5mL, 165mmol) is then successively added, and forms precipitating immediately.By the reaction mixture It is stirred overnight at 45 DEG C.The reaction mixture is cooled to room temperature, which is filtered, is then ground with water, obtains 2- amino- 6- chloro-4-methoxy pyridine -3,5- dimethoxy nitrile (322mg, 1.544mmol, 21% yield), is pale solid.LCMS m/ Z=209.1 [M+H]+。
Step 3:2- ((6- amino -3,5- dicyano -4-methoxypyridine -2- base) sulfenyl) -2- phenyl-acetamides
Thioacetic acid S- (2- amino -2- oxo -1- phenylethyl) ester (in 62 step 5 of embodiment is described into conjunction At 385mg, 1.841mmol) and NaBH4The reaction mixture of (87mg, 2.301mmol) in ethyl alcohol (10mL) adds at 50 DEG C Heat 25 minutes (blistering stops).The reaction mixture is cooled to room temperature to and is added to 2- amino -6- chloro-4-methoxy pyridine -3, 5- dimethoxy nitrile (320mg, 1.534mmol) is in the pulp solution in ethyl alcohol (15mL).The reaction mixture is stirred at room temperature 3 Hour.The solid is filtered, 2- ((6- amino -3,5- dicyano -4-methoxypyridine -2- base) sulfenyl) -2- phenyl second is obtained Amide (517mg, 1.417mmol, 92% yield), is pale solid.LCMS m/z=340.2 [M+H]+。
Step 4:2- ((the chloro- 3,5- dicyano of 6- -4-methoxypyridine -2- base) sulfenyl) -2- phenyl-acetamides
To 2- ((6- amino -3,5- dicyano -4-methoxypyridine -2- base) sulfenyl) -2- phenyl-acetamides (515mg, Copper chloride (II) (377mg, 2.81mmol) 1.518mmol) is added in the pulp solution in acetonitrile (60mL).By the mixture It is heated 5 minutes at 50 DEG C and nitrite tert-butyl (0.334mL, 2.81mmol) is added dropwise.The reaction mixture is heated 4 at 50 DEG C Hour, then it is down to room temperature.The solid is filtered.The filtrate is concentrated, then the residue is mixed and divided with EtOAc and water From each layer.Water layer is extracted twice with EtOA.By combined organic matter water and salt water washing, Na is used2SO4It is dry, concentration.It will The residue is with silica gel purification (40g column uses 0-100%EtOAc/ hexane).Obtained fractions are concentrated and are ground with EtOAc, Obtain 2- ((chloro- 3, the 5- dicyano of 6- -4-methoxypyridine -2- base) sulfenyl) -2- phenyl-acetamides (192mg, 0.503mmol, 33% yield), it is pale solid.LCMS m/z=359.1 [M+H]+。
Step 5:2- ((3,5- dicyano -6- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base) -4- methoxy Yl pyridines -2- base) sulfenyl) -2- phenyl-acetamides
To 2- ((chloro- 3, the 5- dicyano of 6- -4-methoxypyridine -2- base) sulfenyl) -2- phenyl-acetamides (195mg, 2- (1,4- Diazesuberane -1- base) ethane -0.511mmol) is added in the solution in N,N-dimethylformamide (5mL) 1- alcohol (88mg, 0.613mmol).The mixture is stirred at room temperature 4 hours.The reaction mixture is concentrated and uses RP-HPLC Purify (30-50% acetonitrile/water, 0.1%NH4The aqueous solution of OH), obtain 2- ((3,5- dicyano -6- (4- (2- hydroxyethyl) - Isosorbide-5-Nitrae-Diazesuberane -1- base) -4-methoxypyridine -2- base) sulfenyl) -2- phenyl-acetamides (148mg, 0.317mmol, 62% yield), it is white solid.LCMS m/z=467.3 [M+H]+。1H NMR (400MHz, DMSO-d) δ ppm 1.84- 1.92 (m, 2H), 2.52-2.56 (m, 2H), 2.58-2.70 (m, 2H), 2.70-2.89 (m, 2H), 3.47 (q, J=6.2Hz, 2H), 3.78-3.94 (m, 4H), 4.24 (s, 3H), 6 4.39 (t, J=5.3Hz, 1H), 5.51 (s, 1H), 7.29-7.43 (m, 4H), 7.45-7.53 (m, 2H), 7.91 (s, 1H).
Embodiment 143
2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine
Step 1:(1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) piperidin-4-yl) t-butyl carbamate
At -20 DEG C, (conjunction is described in embodiment 3, step 2 to chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- Be added in the suspension in ethyl alcohol (2mL) at 300mg, 1.327mmol) piperidin-4-yl t-butyl carbamate (292mg, 1.460mmol) the solution in ethyl alcohol (2.5mL).Then the reaction mixture is stirred 30 minutes at -20 DEG C.Then to this 0 DEG C is warmed in reaction mixture, then by the thioacetic acid potassium (227mg, 1.991mmol) and Et3N (0.462mL, The reaction mixture 3.32mmol) is added to, and additional ethyl alcohol (5mL) is added.Then by the heterogeneous reaction mixture temperature Heat is stirred overnight to 20 DEG C and mutually synthermal.Methanesulfonic acid 2- amino -2- oxo -1- phenyl second is added into the reaction mixture Base ester (describes synthesis, 608mg, 2.65mmol) in embodiment 3, step 5.After 20 DEG C are stirred 2.5 hours, by the reaction Temperature rises to 40 DEG C.After 40 DEG C are stirred 2.5 hours, which is cooled to room temperature and is filtered.The solid is used Then EtOH, water, EtOH use Et2O washing.Then separated material vacuum drying box is dry, obtain (1- (6- ((2- ammonia Base -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl) the tertiary fourth of carbamic acid Ester 520mg is pale solid.LCMS m/z=521.4 [M+H]+。
Step 2:2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide
By (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) Piperidin-4-yl) t-butyl carbamate (505mg, 0.970mmol) is suspended in the 4M HCl (80mmol) of 20mL in dioxanes Solution in.Then the reaction mixture is stirred at room temperature 2 hours.Then the reaction mixture is concentrated and by the thick material It is suspended in dioxanes and filters the mixture.Solid is washed and dried with dioxanes, white solid is obtained, is suspended It is in MeOH and free-basing with isopropylamine.The mixture reversed-phase HPLC is purified into (Gilson, 30mm x 50mm Gemini Column, NH4OH modifying agent), obtain 2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides (149mg), are white solid.LCMS m/z=421.1 [M+H]+。1H NMR (400MHz, DMSO-d6)δ Ppm7.94 (s, 1H), 7.50-7.54 (m, 2H), 7.31-7.41 (m, 4H), 5.53 (s, 1H), 4.41 (d, J=13.43Hz, 2H), 3.25-3.31 (m, 2H), 2.87-2.96 (m, 1H), 2.75 (q, J=7.60Hz, 2H), 1.84 (d, J=12.42Hz, 2H), 1.24-1.38 (m, 2H), 1.20 (t, J=7.60Hz, 3H).(2H is covered by water).
Embodiment 144
2- ((6- ((2- amino-ethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide, trifluoroacetate
Step 1:(2- ((the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) (methyl) amino) ethyl) carbamic acid The tert-butyl ester
To chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in 3 step 2 of embodiment, 1g, 4.42mmol) in the solution in DCM (50mL) be added (2- (methylamino) ethyl) t-butyl carbamate (0.771g, 4.42mmol) and triethylamine (0.448g, 4.42mmol).The reaction mixture is stirred overnight at 25 DEG C, is then concentrated, obtains (2- ((chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-) (methyl) amino) ethyl) t-butyl carbamate (1.4g, 87% Yield).LCMS m/z=386.1 [M+Na]+。
Step 2:(2- ((3,5- dicyano -4- ethyl -6- mercaptopyridine -2- base) (methyl) amino) ethyl) amino first Tert-butyl acrylate
To (2- ((the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) (methyl) amino) ethyl) the tertiary fourth of carbamic acid Ester (1.4g, 3.85mmol) be added in the solution in n,N-Dimethylformamide (150mL) thioacetic acid potassium (0.714g, 6.25mmol).The reaction mixture is stirred overnight at 25 DEG C.The reaction mixture is concentrated, then loads the residue To silicagel column, it is eluted with DCM/MeOH, obtains (2- ((3,5- dicyano -4- ethyl -6- mercaptopyridine -2- base) (first Base) amino) ethyl) t-butyl carbamate (700mg, 50% yield).LCMS m/z=384.1 [M+Na]+。
Step 3:(2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) (methyl) amino) ethyl) t-butyl carbamate
To (2- ((3,5- dicyano -4- ethyl -6- mercaptopyridine -2- base) (methyl) amino) ethyl) carbamic acid uncle Methanesulfonic acid 2- amino -2- oxo -1- phenylethyl is added in butyl ester (700mg, 1.937mmol) in the solution in DMF (150mL) Ester (describing synthesis, 1g, 4.36mmol in 3 step 5 of embodiment) and potassium acetate (190mg, 1.937mmol).By the reaction Mixture is stirred overnight at 25 DEG C, and water (100mL) is added, and is then extracted with EA (100mL x 3).By the organic phase sulfuric acid Sodium is dry and evaporates.Residue preparative-HPLC is purified, (2- ((6- ((2- amino -2- oxo -1- phenyl second is obtained Base) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) amino) ethyl) t-butyl carbamate (500mg, 1.011mmol, 52% yield).LCMS m/z=517.1 [M+Na]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.82 (s, 1H), 7.45 (m, 6H), 6.93 (s, 1H), 5.58 (s, 1H), 3.81 (s, 2H), 3.40 (s, 3H), 3.21 (s, 2H), 2.76 (s, 2H), 1.34 (s, 9H), 1.20 (s, 3H).
Step 4:2- ((6- ((2- amino-ethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides, trifluoroacetate
To (2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) (methyl) amino) ethyl) t-butyl carbamate (200mg, 0.404mmol) is added 2 in the solution in DCM (30mL), 2,2- trifluoroacetic acids (46.1mg, 0.404mmol).The reaction mixture is stirred overnight at 25 DEG C.The mixture is concentrated, so The residue is further purified with preparative-HPLC afterwards, obtains 2- ((6- ((2- amino-ethyl) (methyl) amino) -3,5- bis- Cyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides, trifluoroacetate (100mg, 48% yield).LCMS m/z= 395.1[M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.01 (s, 1H), 7.93 (s, 3H), 7.56-7.46 (m, 3H), 7.45-7.33 (m, 3H), 5.49 (s, 1H), 4.00 (t, J=6.1Hz, 2H), 3.46 (s, 3H), 3.12 (dt, J=11.4, 5.8Hz, 2H), 2.80 (q, J=7.5Hz, 2H), 1.23 (t, J=7.6Hz, 3H).
Embodiment 145
2- ((6- ((2- amino -2- oxoethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides
At -20 DEG C, under mechanical stirring, to chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (in embodiment 3, step Synthesis, 1.7g, 7.52mmol are described in 2) 2- (methylamino) acetamide, salt are added in the suspension in ethyl alcohol (30mL) Hydrochlorate (1.0g, 8.03mmol) and Et3Solution of the N (2.17mL, 15.57mmol) in ethyl alcohol (30mL).Then by the reaction Mixture stirs 45 minutes at -20 DEG C.Then into the reaction mixture be added thioacetic acid potassium (1.3g, 11.38mmol) and Et3N (2.62mL, 18.80mmol).Then the heterogeneous reaction mixture is warmed to 40 DEG C and in mutually synthermal stirring.? After 40 DEG C are stirred overnight, which is cooled to room temperature.Methanesulfonic acid 2- amino-is added into the room temperature reaction mixture 2- oxo -1- phenylethylester (synthesis, 2.6g, 11.34mmol are described in embodiment 3, step 5).The reaction is warmed It is stirred 3.5 hours to 40 DEG C and in the temperature.The reaction mixture is cooled to 20 DEG C, is then filtered.Then the solid is used 300mL EtOH washing, then uses 300mL water washing.Then gained white solid is washed with EtOH (200mL) again, then With 100mL Et2O washing.Then the solid is dried in vacuum overnight in vacuum drying oven, obtains 2- ((6- ((2- amino -2- oxygen For ethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides (1.53g, 3.75mmol, 50% yield), it is white solid.LCMS m/z=409.3 [M+H]+。1H NMR (400MHz, DMSO-d6)δ Ppm 7.83 (s, 1H), 7.62 (s, 1H), 7.47-7.53 (m, 2H), 7.32-7.42 (m, 5H), 5.59 (s, 1H), 4.52 (d, J =17.49Hz, 1H), 4.29 (d, J=17.24Hz, 1H), 3.39 (s, 3H), 2.77 (q, J=7.60Hz, 2H), 1.21 (t, J =7.48Hz, 3H).
Embodiment 146
2- ((3,5- dicyano -4- ethyl -6- (3- hydroxy azetidine -1- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide
The chloro- 4- ethyl -6- of step 1:2- (3- hydroxy azetidine -1- base) pyridine -3,5- dimethoxy nitrile
To chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in 3 step 2 of embodiment, 300mg, Triethylamine (0.366mL, 2.63mmol) 1.31mmol) is added in the solution in methylene chloride (10mL), azepine is then added Cyclobutane -3- alcohol hydrochloride (144mg, 1.31mmol).The reaction mixture is stirred at room temperature 30 minutes.The reaction is mixed Object is diluted with DCM (30mL).Organic layer is washed with water (20mL) and saturated brine solution (20mL).By the anhydrous sulphur of organic layer Sour sodium dries, filters, and evaporation obtains the chloro- 4- ethyl -6- of 2- (3- hydroxy azetidine -1- base) pyridine -3,5- dimethoxy nitrile (300mg) is pale solid.LCMS m/z=263.0 [M+H]+。
Step 2:2- ((3,5- dicyano -4- ethyl -6- (3- hydroxy azetidine -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides
By the chloro- 4- ethyl -6- of 2- (3- hydroxy azetidine -1- base) pyridine -3,5- dimethoxy nitrile (300mg, 0.994mmol) it is dissolved in n,N-Dimethylformamide (20mL) with thioacetic acid potassium (227mg, 1.987mmol) and is stirred at room temperature 2 hours.Then 0 DEG C by potassium carbonate (275mg, 1.987mmol) and methanesulfonic acid 2- amino -2- oxo -1- phenylethylester ( Synthesis, 485mg, 1.987mmol are described in 3 step 5 of embodiment) add to the reaction mixture.By the reaction mixture in room Temperature is stirred overnight.Reaction mixture HCl solution (1N, 100mL) and ethyl acetate (80mL) are diluted.Organic layer is separated, It is dried, filtered, is evaporated with anhydrous sodium sulfate.Raw product is used into silica gel purification (100-200 mesh, with the DCM of 3-4% methanol Solution elution), obtain 2- ((3,5- dicyano -4- ethyl -6- (3- hydroxy azetidine -1- base) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides (120mg), are brown solid.LCMS m/z=394.2 [M+H]+。1H NMR (400MHz, DMSO-d6)δ Ppm 7.84 (br s, 1H), 7.51 (d, J=6.80Hz, 2H), 7.41-7.16 (m, 4H), 5.87 (br d, J=5.70Hz, 1H), 5.55 (s, 1H), 4.74-4.37 (m, 3H), 4.16 (m, 2H), 2.69 (q, J=7.45Hz, 2H), 1.18 (t, J= 7.56Hz, 3H).
Embodiment 147
2- (3,5- dicyano -4- ethyl -6- ((2- hydroxyethyl) (methyl) amino) pyridine -2- base sulfenyl) -2- phenyl Acetamide
The chloro- 4- ethyl -6- of step 1:2- ((2- hydroxyethyl) (methyl) amino) pyridine -3,5- dimethoxy nitrile
At 0 DEG C, to chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (in 3 step 2 of embodiment describe synthesis, 4.3g, 19.02mmol) addition triethylamine (7.95mL, 57.1mmol) in the solution in methylene chloride (50mL), then it is added 2- (methylamino) ethyl alcohol (1.43g, 19.02mmol).The mixture is warmed to 25 DEG C and is stirred 16 hours.By the mixture It pours into water (30mL) and is extracted with DCM (25mL x 2).Organic phase is concentrated, then the residue is purified with column chromatography, Using DCM/MeOH (100/1), the chloro- 4- ethyl -6- of 2- ((2- hydroxyethyl) (methyl) amino) pyridine -3,5- diformazan is obtained Nitrile, for brown solid (5.1g, 86% yield).LCMS m/z=265.0 [M+H]+。
Step 2:2- (3,5- dicyano -4- ethyl -6- ((2- hydroxyethyl) (methyl) amino) pyridine -2- base sulfenyl) - 2- phenyl-acetamides
To the chloro- 4- ethyl -6- of 2- ((2- hydroxyethyl) (methyl) amino) pyridine -3,5- dimethoxy nitrile (2.1g, Thioacetic acid potassium (1.359g, 11.90mmol) 7.93mmol) is added in the solution in n,N-Dimethylformamide (15mL), Then K is added2CO3(3.29g, 23.80mmol).The mixture is stirred 16 hours at 25 DEG C, methanesulfonic acid 2- ammonia is then added Base -2- oxo -1- phenylethylester (describing synthesis, 1.923g, 8.39mmol in 3 step 5 of embodiment) is in N, N- diformazan Solution in base formamide (20mL).The mixture is stirred 16 hours at 25 DEG C.The mixture is poured into water (40mL) simultaneously It is extracted with ethyl acetate (40mL x 2).The organic phase is concentrated into dry doubling the residue is purified with column chromatography, uses DCM/ MeOH (50/1) obtains 2- ((3,5- dicyano -4- ethyl -6- ((2- hydroxyethyl) (methyl) amino) pyridine -2- base) sulphur Base) -2- phenyl-acetamides (600mg, 1.517mmol, 18% yield) are light yellow solid.LCMS m/z=396.1 [M+ H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.94 (s, 1H), 7.51 (d, J=8Hz, 2H), 7.31-7.40 (m, 4H), 5.55 (s, 1H), 4.86 (m, 1H), 3.86 (m, 2H), 3.62 (m, 2H), 3.40 (s, 3H), 2.75 (m, 2H), 1.21 (m, 3H).
Embodiment 148:
2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) -2- methyl propanamide
Step 1:(1- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine-2- base) piperidin-4-yl) amino)-2- methyl-1-oxo propyl- 2- yl) t-butyl carbamate
By 2- ((tertbutyloxycarbonyl) amino) -2 Methylpropionic acid (410mg, 2.017mmol) and HATU (1151mg, It 3.03mmol) is dissolved in n,N-Dimethylformamide (4mL) and triethylamine (408mg, 4.03mmol) is added.Then 2- ((6- is added (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides (in embodiment 143, Synthesis, 848mg, 2.017mmol are described in step 2).The solution is stirred at room temperature 12 hours.By the solution water The dilution of (60mL) and ethyl acetate (60mL).Organic phase is washed with water (30mL) and salt water (30mL), dry, concentration, then The residue is purified on a silica gel column, using ethyl acetate, obtains (1- ((1- (6- ((2- amino -2- oxo -1- phenyl second Base) sulfenyl)-3,5- dicyano-4- ethylpyridine-2- base) piperidin-4-yl) amino)-2- methyl-1-oxo propyl- 2- yl) amino T-butyl formate (900mg, 74% yield), is white solid.LCMS m/z=628.2 [M+Na]+。
Step 2:2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- Ethylpyridine -2- base) piperidin-4-yl) -2- methyl propanamide
By (1- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) piperidin-4-yl) amino)-2- methyl-1-oxo propyl- 2- yl) t-butyl carbamate (850mg, 1.403mmol) is dissolved in Trifluoroacetic acid (1mL) is in the solution in methylene chloride (10mL).The solution is stirred at room temperature 3 hours.The solution is used full And NaHCO3Solution (30mL) is quenched and is extracted with ethyl acetate (30mL).By the organic phase water (30mL) and salt water (30mL) Washing, dry, then which is purified on a silica gel column, using DCM/MeOH (10/1), obtains 2- amino-N- by concentration (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl) - 2- methyl propanamide (129mg, 18% yield), is white solid.LCMS m/z=506.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.93 (s, 1H), 7.77 (d, J=8.0Hz, 1H), 7.52 (d, J=7.2Hz, 2H), 7.45-7.28 (m, 4H), 5.54 (s, 1H), 4.49 (t, J=13.4Hz, 2H), 3.97-3.78 (m, 1H), 3.37-3.24 (m, 3H), 2.77 (q, J =7.5Hz, 2H), 2.02 (s, 2H), 1.87 (d, J=12.1Hz, 2H), 1.64-1.42 (m, 2H), 1.28-1.14 (m, 9H).
Embodiment 149
2- ((6- (4- (2- amino ethoxy) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides, trifluoroacetate
Step 1:(2- (piperidin-4-yl oxygroup) ethyl) t-butyl carbamate
(2- (pyridin-4-yl oxygroup) ethyl) t-butyl carbamate (1.9g, 7.97mmol) is dissolved in acetic acid (20mL) And platinum oxide (IV) (0.030g, 0.132mmol) is added.By the mixture in H2It is stirred 12 hours under (0.4MPa).This is mixed It closes object to filter and the filtrate is concentrated, obtaining (2- (piperidin-4-yl oxygroup) ethyl) t-butyl carbamate, (2g, 98% produces Rate).1H NMR (400MHz, DMSO-d6) δ ppm 6.84 (s, 1H), 3.49-3.45 (m, 1H), 3.39-3.36 (m, 2H), 3.36-3.33 (m, 4H), 2.79-2.73 (m, 2H), 1.86-1.80 (m, 2H), 1.56 (m, 2H), 1.37 (s, 9H).
Step 2:(2- ((1- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) piperidin-4-yl) oxygroup) ethyl) ammonia Base t-butyl formate
By chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in 3 step 2 of embodiment, 925mg, 4.09mmol) and (2- (piperidin-4-yl oxygroup) ethyl) t-butyl carbamate (1000mg, 0.409mmol) is dissolved in DCM (20mL) and triethylamine (0.507mL, 4.09mmol) is added.The solution is stirred at room temperature 12 hours.Water (20mL) is added simultaneously Isolated organic phase is washed with salt water (30mL), is dried and concentrated to obtain (2- ((1- (chloro- 3, the 5- dicyano -4- ethyl pyrrole of 6- Pyridine -2- base) piperidin-4-yl) oxygroup) ethyl) t-butyl carbamate (1360mg, 77% yield).LCMS:m/z=456.1 [M +Na]+。
Step 3:(2- ((1- (5- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -2,4- dicyano -3- ethylo benzene Base) piperidin-4-yl) oxygroup) ethyl) t-butyl carbamate
By (2- ((1- (the chloro- 2,4- dicyano -3- ethylphenyl of 5-) piperidin-4-yl) oxygroup) ethyl) carbamic acid uncle Butyl ester (300mg, 0.691mmol) be dissolved in n,N-Dimethylformamide (6mL) and be added thioacetic acid potassium (118mg, 1.037mmol).The solution is stirred at room temperature 1 hour, K2CO3 (191mg, 1.383mmol) then is added.By the mixture It is stirred at room temperature 1 hour, methanesulfonic acid 2- amino -2- oxo -1- phenylethylester is then added and (is described in 3 step 5 of embodiment Synthesis, 238mg, 1.037mmol).The mixture is stirred at room temperature 12 hours.The mixture is diluted with water and uses acetic acid Ethyl ester (40mL) extraction.The organic phase is washed with salt water (30mL), is dried and concentrated, then on a silica gel column by the residue Purifying, using petrol ether/ethyl acetate (1/1), obtains (2- ((1- (5- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) - 2,4- dicyano -3- ethylphenyls) piperidin-4-yl) oxygroup) ethyl) t-butyl carbamate (300mg, 77% yield). LCMS:m/z=586.8 [M+Na]+。
Step 4:2- ((6- (4- (2- amino ethoxy) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base) Sulfenyl) -2- phenyl-acetamides, trifluoroacetate
By (2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) piperidin-4-yl) oxygroup) ethyl) t-butyl carbamate (300mg, 0.531mmol) adds in methylene chloride (20mL) And solution of 2,2, the 2- trifluoroacetic acids (100mg, 0.877mmol) in 5mL methylene chloride is added at 0 DEG C.The mixture is stirred It mixes overnight, is then concentrated.Residue preparative-HPLC is purified, 2- ((6- (4- (2- amino ethoxy) piperidines-is obtained 1- yl) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides, (100mg, 33% produces trifluoroacetate Rate).LCMS m/z=465.1 [M+H]+。1H NMR (400MHz, DMSO-d6): δ ppm7.93 (s, 1H), 7.82 (s, 2H), 7.53 (d, J=7.2Hz, 2H), 7.41-7.34 (m, 4H), 5.53 (s, 1H), 4.12 (m, 2H), 3.70-3.62 (m, 5H), 3.03 (m, 2H), 2.75 (m, 2H), 1.95 (m, 2H), 1.61 (m, 2H), 1.23 (t, J=7.6Hz, 3H).
Embodiment 150
Biphosphate 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) pyrrolidin-3-yl ester
To 2- ((3,5- dicyano -4- ethyl -6- (3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl Acetamide (synthesis, 400mg, 0.911mmol are described in embodiment 370, step 2) triethylamine (0.190mL, Triethyl phosphate (4mL, 0.911mmol) is added in stirring suspension in 1.367mmol) and is cooled to the reaction mixture 0℃.After five minutes, POCl is added3(0.127mL, 1.367mmol) and the reaction mixture is vigorously stirred 1.5 hours at 0 DEG C. The reaction mixture is quenched with water (1.5mL) and is stirred 10 minutes.The reaction mixture is purified with Grace device and will be pure Fraction concentration, obtain 110mg (peak two of them LC correspond to 65% and 14% abundance two diastereoisomers). (peak two of them LC is corresponding for the material mixing from independent batch that above-mentioned 110mg product and 300mg are prepared in a similar manner In two diastereoisomers with 14% and 19% abundance) and carry out preparative-HPLC purifying.The pure fraction is frozen It is dry, the pale solid of 70mg is obtained, display triethyl phosphate remains peak.By the hexane (6mL) of solid 5%EtOAc Then grinding is ground with the hexane solution (2x 5mL) of 10%EtOAc, is finally ground with the hexane solution of 20%EtOAc (6mL) Mill.The solid is dried in vacuo, biphosphate 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- bis- is obtained Cyano -4- ethylpyridine -2- base) pyrrolidin-3-yl ester (62mg) is gray solid.LCMS m/z=486.3 [M-H]–.1H NMR(D2O-Exchange) (400MHz, DMSO-d6) δ ppm 7.58-7.51 (m, 2H), 7.44-7.32 (m, 3H), 5.68- 5.58 (m, 1H), 4.80-4.76 (m, 1H), 4.09-3.86 (m, 4H), 2.76-2.72 (m, 2H), 2.20-2.16 (m, 1H), 2.07-1.99 (m, 1H), 1.29-1.11 (m, 3H).
Embodiment 151
Biphosphate 2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) (methyl) amino) ethyl ester
To 2- ((3,5- dicyano -4- ethyl -6- ((2- hydroxyethyl) (methyl) amino) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides (describing synthesis, 300mg, 0.759mmol in 147 step 2 of embodiment) triethylamine (159 μ L, Triethyl phosphate (2583 μ L, 15.17mmol) is added in suspension in 1.138mmol) and the mixture is cooled to 0 DEG C. Then phosphinylidyne trichlorine (174mg, 1.138mmol) is added and is vigorously stirred the mixture 1.5 hours at 0 DEG C.The reaction is mixed Object is closed to be quenched and stirred 10 minutes with water (1.5mL).Then it is alkalized with NaOH (1M, 20mL), with ethyl acetate (40mL) It dilutes and stirs 10 minutes.It separates each layer and water layer HCl (1N, 50mL) is acidified and is extracted with ethyl acetate (3x 50mL). Organic layer with Na2SO4 drying and is concentrated in vacuo, the crude compound of 90mg is obtained, it is purified with preparative-HPLC.It will The pure fraction freeze-drying obtains 15mg, is pale solid.The material is merged with the product of the independent batch of 7mg.By the conjunction And material be dissolved in acetonitrile (2mL) and water (5mL).The solution is freezed and is lyophilized, biphosphate 2- ((6- ((2- ammonia is obtained Base -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) amino) ethyl ester (15mg) is pale solid.LCMS m/z=474.3 [M-H]-。1H NMR (400MHz, DMSO-d6)δppm 9.87(br S, 1H), 7.96-7.60 (m, 2H), 7.31-7.27 (m, 3H), 6.94 (br s, 1H), 6.52 (br s, 1H), 6.24 (br s, 1H), 6.10 (s, 1H), 4.00-3.88 (m, 2H), 3.86-3.72 (m, 2H), 3.40 (s, 3H), 2.74 (q, J=7.5Hz, 2H), 1.19 (t, J=7.6Hz, 3H).
Embodiment 152
Biphosphate 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) azetidine -3- base ester
At 0 DEG C, by POCl3(0.067mL, 0.716mmol) is added dropwise to 2- ((3,5- dicyano -4- ethyl -6- (3- hydroxyls Azetidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides (synthesis is described in 146 step 2 of embodiment, 200mg, 0.477mmol), the mixing of triethylamine (0.100mL, 0.716mmol) and triethyl phosphate (0.5mL, 0.477mmol) In object.By the reaction mixture in mutually synthermal stirring 1 hour.The reaction mixture is quenched with simultaneously cold water (50mL) and should The pH of reaction mixture is adjusted to pH~11 by being slowly added to NaOH (1N, 40mL).Then by the reaction mixture acetic acid Ethyl ester (2x 30mL) washing.Then water layer HCl (1N, 30mL) is slowly acidified to pH~1 and with ethyl acetate (2x 50mL) extract.By combined organic layer anhydrous Na2SO4It is dried, filtered and concentrated.By gained residue preparative-HPLC Purifying.Then by pure fraction freeze-drying and drying, biphosphate 1- (6- ((2- amino -2- oxo -1- phenylethyl) is obtained Sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) azetidine -3- base ester (54mg, 24% yield), it is solid for white Body.LCMS m/z=472.3 [M-H]–.1H NMR (400MHz, DMSO-d6): δ ppm 8.25 (s, 1H), 7.72-7.52 (m, 2H), 7.44-7.26 (m, 3H), 7.20 (s, 1H), 6.75 (bs, 2H), 5.63 (s, 1H), 4.89-4.77 (m, 1H), 4.77- 4.56 (m, 2H), 4.41-4.24 (m, 2H), 2.66 (q, J=7.7Hz, 2H), 1.16 (t, J=7.6Hz, 3H).
Embodiment 153:
(2S) -2- amino -3 Methylbutanoic acid 2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- Dicyano -4- ethylpyridine -2- base) piperidin-4-yl) oxygroup) ethyl ester
Step 1:(2S) -2- ((tertbutyloxycarbonyl) amino) -3 Methylbutanoic acid 2- ((1- (6- ((2- amino -2- oxo - 1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl) oxygroup) ethyl ester
In room temperature, to 1H- benzo [d] [1,2,3] triazole -4- alcohol (0.058g, 0.430mmol), (S) -2- ((tertiary fourth oxygen Carbonyl) amino) -3 Methylbutanoic acid (0.560g, 2.58mmol) and EDC (0.494g, 2.58mmol) be at methylene chloride (10mL) In solution in be added triethylamine (0.261g, 2.58mmol).Gained mixture is stirred at room temperature 1 hour, 2- is then used ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxyl-oxethyl) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- phenyl-acetamides (synthesis, 0.2g, 0.430mmol are described in embodiment 224, step 4) processing.Gained mixture was stirred at room temperature Then night is concentrated in vacuo.Residue silica gel column purification is obtained into (2S) -2- ((tertiary fourth oxygen using DCM/MeOH (50/1) Carbonyl) amino) -3 Methylbutanoic acid -2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- Ethylpyridine -2- base) piperidin-4-yl) oxygroup) ethyl ester (250mg).LCMS m/z=687.2 [M+Na]+。
Step 2:(2S) -2- amino -3 Methylbutanoic acid 2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulphur Base) -3,5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl) oxygroup) ethyl ester
In room temperature, to (2S) -2- ((tertbutyloxycarbonyl) amino) -3 Methylbutanoic acid -2- ((1- (6- ((2- amino -2- oxygen Generation -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl) oxygroup) ethyl ester (230mg, 2,2,2- trifluoroacetic acids (394mg, 3.46mmol) 0.346mmol) are added in the solution in methylene chloride (5mL).By gained Mixture is stirred at room temperature overnight, and is then concentrated in vacuo, and is then diluted the residue with EtOAc (50mL) and is used unsaturated carbonate Hydrogen sodium water solution (25mL), water (10mL) and saturated brine (10mL) washing, with sodium sulphate drying and are evaporated in vacuo.By crude production Object adds to silicagel column and is eluted with DCM/MeOH (30/1), obtains (2S) -2- amino -3 Methylbutanoic acid 2- ((1- (6- ((2- ammonia Base -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl) oxygroup) ethyl ester (120mg, 59% yield).LCMS m/z=565.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.93 (s, 1H), 7.52 (d, J=7.2Hz, 2H), 7.44-7.30 (m, 4H), 5.53 (s, 1H), 4.26 (m, 1H), 4.19-4.05 (m, 3H), 3.74-3.55 (m, 5H), 3.16 (s, 1H), 2.76 (q, J=7.5Hz, 2H), 2.03-1.77 (m, 5H), 1.62-1.48 (m, 2H), 1.22 (t, J=7.6Hz, 3H), 0.88 (dd, J=15.8,6.8Hz, 6H).
Embodiment 154:
Biphosphate 2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl Pyridine -2- base) piperidin-4-yl) oxygroup) ethyl ester
At 0 DEG C, by the mixed of triethyl phosphate (58.7mg, 0.322mmol) and phosphinylidyne trichlorine (148mg, 0.967mmol) Object is closed in 0 DEG C of stirring and after 10 minutes by gained mixture 2- ((3,5- dicyano -4- ethyl -6- (4- (2- '-hydroxyethoxy Base) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- phenyl-acetamides (synthesis is described in embodiment 224, step 4, 150mg, 0.322mmol) processing.Gained mixture is stirred 1 hour at 0 DEG C, is then stirred at room temperature 2 hours, then with broken Ice is quenched.Gained mixture is dissolved in Me-CN (10mL) and is purified with preparative HPLC and (is washed with Me-CN/ formic acid 0.1% It is de-), obtain biphosphate 2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) oxygroup) ethyl ester (90mg, 0.163mmol, 51% yield).LCMS m/z=546.0 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 11.55-10.42 (br, 2H), 7.94 (s, 1H), 7.52 (d, J=7.3Hz, 2H), 7.43-7.31 (m, 4H), 5.53 (s, 1H), 4.17-4.07 (m, 2H), 3.94 (m, 2H), 3.72-3.56 (m, 5H), 2.76 (m, 2H), 1.99-1.89 (m, 2H), 1.63-1.51 (m, 2H), 1.21 (t, J=7.6Hz, 3H).
Embodiment 155
Biphosphate 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) piperidin-4-yl ester
At 0 DEG C, by POCl3(0.130mL, 1.392mmol) is added dropwise to 2- ((3,5- dicyano -4- ethyl -6- (4- hydroxyls Piperidin-1-yl) pyridine -2- base) sulfenyl) -2- phenyl-acetamides (describe synthesis in embodiment 48,400mg, 0.928mmol), in the mixture of triethylamine (0.194mL, 1.392mmol) and triethyl phosphate (4mL, 23.50mmol) and will The reaction mixture was in mutually synthermal stirring 1 hour.After 1 hour, be added dropwise at 0 DEG C additional triethylamine (0.194mL, 1.392mmol) and POCl3(0.130mL, 1.392mmol) and in mutually synthermal stirring 1 hour.By the reaction mixture ice Cold water (70mL) is quenched and the pH of the reaction mixture is adjusted to pH~11 by being slowly added to NaOH (1N, 50mL).It should Solution is washed with EtOAc (2x 30mL).Then water layer is slowly acidified to pH~1 with HCl (1N, 30mL) and uses EtOAc (2x 50mL) extraction.By combined organic layer anhydrous Na2SO4It dries, filters, is concentrated and dries, obtain the crude product.It should Crude material carries out preparative HPLC and by pure fraction freeze-drying and drying, obtains biphosphate 1- (6- ((2- amino -2- oxygen Generation -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl ester (90mg, 19% yield), For white solid.LCMS m/z=500.1 [M-H]-1H NMR (400MHz, DMSO-d6) δ ppm 8.03 (br s, 1H), 7.58-7.44 (m, 2H), 7.40-7.25 (m, 4H), 5.56 (s, 1H), 4.36-4.27 (m, 1H), 4.04-3.93 (m, 2H), 3.81-3.71 (m, 2H), 2.74 (q, J=7.67Hz, 2H), 1.99-1.83 (m, 2H), 1.70 (m, 2H), 1.19 (t, J= 7.56Hz, 3H).
Embodiment 156
N- (4- (((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) methyl) benzyl Base) acetamide, trifluoroacetate
Step 1:(1- (6- ((4- (acetylamino methyl) benzyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) Piperidin-4-yl) t-butyl carbamate
To (1- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) piperidin-4-yl) t-butyl carbamate (in reality Apply in 81 step 1 of example and describe synthesis, 3g, 7.69mmol) it is added in the solution in n,N-Dimethylformamide (50mL) K2CO3Then thioacetic acid potassium (0.879g, 7.69mmol) is added in (1.063g, 7.69mmol).The mixture is stirred at 25 DEG C It mixes 2 hours, and for next step, without being further purified.LCMS m/z=410.1 [M+Na]+。
Step 2:(1- (6- ((4- (acetylamino methyl) benzyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) Piperidin-4-yl) t-butyl carbamate
Into said mixture (embodiment 156, step 1) addition N- (4- (bromomethyl) benzyl) acetamide (6g, 12.39mmol).The mixture is stirred 16 hours at 25 DEG C.The mixture is filtered and is concentrated.By residue acetic acid second Ester (40mL) is diluted and is washed with water (20mL).The organic phase is concentrated, then the residue is purified with column chromatography, is used Then the product is recrystallized with ethyl acetate-light petrol (1/1), obtains (1- (6- ((4- (acetyl ammonia by DCM-MeOH (50/1) Ylmethyl) benzyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl) t-butyl carbamate (3.3g, It 6.01mmol), is yellow solid.LCMS m/z=549.2 [M+H]+。
Step 3:N- (4- (((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) first Base) benzyl) acetamide, trifluoroacetate
At 0 DEG C, to (1- (6- ((4- (acetylamino methyl) benzyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) piperidin-4-yl) TFA is added in the solution in methylene chloride (30mL) in t-butyl carbamate (2.9g, 5.29mmol) (3.26mL, 42.3mmol).The mixture is warmed to 25 DEG C and is stirred 4 hours.The mixture is concentrated, then by the remnants Object is diluted with t-butyl methyl ether (30mL).The mixture is stirred 1 hour and filtered, N- (4- (((6- (4- amino piperazine is obtained Pyridine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) methyl) benzyl) acetamide, trifluoroacetate (2g) is Pale solid.LCMS m/z=449.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.37 (br, 1H), 8.10 (s, 3H), 7.36 (d, J=8Hz, 2H), 7.21 (d, J=8Hz, 2H), 4.49-4.56 (m, 4H), 4.22 (m, 2H), 3.27 (m, 2H), 2.77 (m, 2H), 2.04 (m, 2H), 1.87 (s, 3H), 1.54 (m, 2H), 1.22 (m, 3H).
Embodiment 157:
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (piperidin-4-yl) second Amide
Step 1:4- (2- methoxyl group -2- oxoethyl) piperidines -1- t-butyl formate
Triethylamine (6.44g, 63.6mmol) is added into 2- (piperidin-4-yl) methyl acetate (4.0g, 25.4mmol) two In solution in chloromethanes (35mL).Then in 0 DEG C of dropwise addition di-tert-butyl dicarbonate (8.33g, 38.2mmol).The reaction is mixed It closes object to stir 3 hours at 0 DEG C, then be stirred at room temperature overnight.After being washed with water (3x 50mL), vacuum concentration obtains 4- (2- Methoxyl group -2- oxoethyl) piperidines -1- t-butyl formate (5.7g, 22mmol, 87% yield) is white solid.LCMS M/z=158.1 [M+H-100]+。
Step 2:4- (the bromo- 2- methoxyl group -2- oxoethyl of 1-) piperidines -1- t-butyl formate
At -78 DEG C, 4- (2- methoxyl group -2- oxoethyl) piperidines -1- t-butyl formate (5.0g, 19.43mmol) is existed Solution in THF (5mL) adds to LHMDS (1.0M is in THF) (35.0mL, 35.0mmol) and by the reaction mixture -78 DEG C stirring 3 hours.Bis- (trimethyl silyl) lithium amides (5.86g, 35mmol) are added dropwise and stir the mixture at -78 DEG C 1 hour, bromine (3.76g, 23.5mmol) then is added dropwise.The mixture is stirred 2 hours at -78 DEG C, is then warmed to 0 DEG C and again Stirring 30 minutes.The mixture is diluted with ethyl acetate and uses saturation NaHCO3Solution washing, then uses H2O washing.This is had Machine object Na2SO4It is dry, then desiccant is filtered to and is removed in vacuum solvent, obtain 4- (the bromo- 2- methoxyl group -2- oxo second of 1- Base) piperidines -1- t-butyl formate (5.7g, 10mmol, 52% yield) is yellow oil.LCMS m/z=358.1 [M+Na]+。
Step 3:4- (the bromo- 2- oxoethyl of 2- amino -1-) piperidines -1- t-butyl formate
Solution of the lithium hydroxide (0.236g, 9.81mmol) in water (7.0mL) is added into 4- (the bromo- 2- methoxyl group-of 1- 2- oxoethyl) piperidines -1- t-butyl formate (2.2g, 6.5mmol) is in the solution in MeOH (21mL) and THF (7mL).It will The reaction mixture is stirred at room temperature 3 hours.The solvent in vacuo is removed, white solid is obtained, it is acidified with 1N HCl.It will Raw product is extracted with ethyl acetate and is washed with brine the organic matter and uses Na2SO4It is dry.By desiccant filtering and should Solvent in vacuo removes, and obtains the bromo- 2- of 2- (1- (tertbutyloxycarbonyl) piperidin-4-yl) acetic acid (1.0g), is yellow oil.By the material Material is in next step without being further purified.By triethylamine (0.471g, 4.66mmol) and isobutyl chlorocarbonate (0.636g, The bromo- 2- of 2- (1- (tertbutyloxycarbonyl) piperidin-4-yl) acetic acid (1.0g, 3.10mmol) 4.66mmol) is added in 25mL dichloromethane In cooling (0 DEG C) solution in alkane.The reaction mixture is warmed to room temperature and is stirred 15 minutes under nitrogen atmosphere.Hydrogen-oxygen is added Change ammonium (7.01g, 200mmol).The reaction mixture is stirred 5 minutes.By reaction mixture sodium bicarbonate aqueous solution (1x 10mL), 1N HCl solution (15mL) and salt water (10mL) washing.Merge organic layer, is dried, filtered and depressurized dense with magnesium sulfate Contracting, obtains 4- (the bromo- 2- oxoethyl of 2- amino -1-) piperidines -1- t-butyl formate (1g, 1.87mmol), is yellow oil. LCMS m/z=343.0 [M+Na]+。
Step 4:4- (2- amino -1- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) - 2- oxoethyl) piperidines -1- t-butyl formate
It (is described in embodiment 3, step 3 to 2- chloro- 6- (dimethylamino) -4- ethylpyridine -3,5- dimethoxy nitrile Synthesis, 0.482g, 2.06mmol) in the solution in n,N-Dimethylformamide (25mL) be added thioacetic acid potassium (0.256g, 2.24mmol).The reaction mixture is stirred at room temperature 30 minutes, then by 4- (the bromo- 2- oxoethyl of 2- amino -1-) piperazine Pyridine -1- t-butyl formate (1.0g, 1.9mmol) and triethylamine (0.473g, 4.67mmol) add in the reaction.The reaction is mixed Object is closed to be stirred at room temperature overnight.The mixture is poured into 30mL water.Acquired solution 3x 20mL ethyl acetate is extracted.It will Organic layer merges, and with aqueous sodium carbonate and salt water washing, drying is simultaneously concentrated in vacuo, obtains raw product, be yellow oil.It will The residue loading is eluted to silicagel column and with ethyl acetate/hexane (1:2), obtains 4- (2- amino -1- ((3,5- dicyanos - 6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- oxoethyl) piperidines -1- t-butyl formate (350mg, It 0.74mmol), is yellow solid.LCMS m/z=495.1 [M+Na]+。
Step 5:2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (piperidines -4- Base) acetamide
To 4- (2- amino -1- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- oxygen For ethyl) trifluoroacetic acid is added in the solution in DCM (3mL) in piperidines -1- t-butyl formate (350mg, 0.74mmol) Then the reaction mixture is stirred at room temperature overnight by (3.0mL).The solvent and TFA are removed under reduced pressure, yellow solid is obtained. Solid preparative-TLC is purified, 2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulphur is obtained Base) -2- (piperidin-4-yl) acetamide (220mg, 0.57mmol, 76% yield) is yellow solid.LCMS m/z=373.1 [M+H]+。1H NMR (400MHz, MeOD) δ ppm 4.49 (d, J=6.7Hz, 1H), 3.42 (s, 6H), 3.18-3.11 (m, 2H), 2.91 (q, J=7.6Hz, 2H), 2.72-2.60 (m, 2H), 2.23-2.12 (m, 1H), 1.96-1.90 (m, 1H), 1.88-1.80 (m, 1H), 1.65-1.53 (m, 1H), 1.51-1.40 (m, 1H), 1.31 (t, J=7.6Hz, 4H).
Embodiment 158:
2- ((3,5- dicyano -4- ethyl -6- (4- (sulfonyl propyl base) piperazine -1- base) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides
In room temperature, by 2- [(3,5- dicyano -4- ethyl -6- piperazine -1- base -2- pyridyl group) sulfanyl] -2- phenyl - Solution N, N- diisopropyl of the acetamide (synthesis, 36mg, 0.09mmol are described in embodiment 55) in DCM (5mL) Ethamine (0.02mL, 0.11mmol) processing, is then handled with 1- propanesulfonic acid chloride (0.01mL, 0.11mmol).Add after 20 hours Enter additional n,N-diisopropylethylamine (0.004mL, 0.02mmol) and 1- propanesulfonic acid chloride (0.003mL, 0.02mmol).Again After 2 hours, which is diluted with EtOAc (15mL), with NaOH aqueous solution (1M, 5mL), water (5mL), HCL aqueous solution (2M, 5mL), water (5mL) and salt water washing, are then dried and concentrated by Hydrophobic glass funnel.Obtained solid is ground with ether Mill, obtains 2- [[3,5- dicyano -4- ethyl -6- (4- sulfonyl propyl base piperazine -1- base) -2- pyridyl group] sulfanyl] -2- benzene Base-acetamide (33mg, 73% yield), is pale solid.LCMS m/z=513.2 [M+H]+。1H NMR (300MHz, DMSO-d6, D2O exchange) δ ppm 7.55-7.46 (m, 2H), 7.44-7.32 (m, 3H), 5.50 (s, 1H), 4.01-3.86 (m, 4H), 3.35-3.22 (m, 4H), 3.03 (br t, J=8.8Hz, 2H), 2.76 (q, J=7.4Hz, 2H), 1.77-1.61 (m, 2H), 1.19 (br t, J=7.5Hz, 3H), 0.98 (t, J=7.4Hz, 3H).
Embodiment 159:
2- ((3,5- dicyano -4- ethyl -6- (4- (phenyl sulfonyl) piperazine -1- base) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides
In room temperature, by 2- [(3,5- dicyano -4- ethyl -6- piperazine -1- base -2- pyridyl group) sulfanyl] -2- phenyl - Suspension N, N- diisopropyl of the acetamide (synthesis, 25mg, 0.06mmol are described in embodiment 55) in DCM (2mL) Base ethamine (0.013mL, 0.080mmol) processing, is then handled with benzene sulfonyl chloride (0.009mL, 0.07mmol).After 20 hours, By the mixture with EtOAc (10mL) dilute, with NaOH aqueous solution (0.5M, 5mL), water (5mL), HCL aqueous solution (2M, 5mL), Water (5mL) and salt water washing, are then dried and concentrated by Hydrophobic glass funnel.By the residue triturated under ether, 2- is obtained [[6- [4- (benzenesulfonyl) piperazine -1- base] -3,5- dicyano -4- ethyl -2- pyridyl group] sulfanyl] -2- phenvl-acetamide (31mg, 92% yield), is pale solid.LCMS m/z=547.2 [M+H]+。1H NMR (300MHz, DMSO-d6)δ Ppm 7.90 (s, 1H), 7.79-7.64 (m, 5H), 7.51-7.31 (m, 6H), 5.48 (s, 1H), 4.05-3.89 (m, 4H), 3.09-2.94 (m, 4H), 2.72 (q, J=7.3Hz, 2H), 1.16 (t, J=7.6Hz, 3H).
Embodiment 160:
2- ((3,5- dicyano -4- ethyl -6- ((R) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide
By 2- [(the bromo- 3,5- dicyano -4- ethyl -2- pyridyl group of 6-) sulfanyl] -2- phenvl-acetamide (in embodiment 6, describe synthesis, 17mg, 0.04mmol in step 1) solution in THF (1mL) with (R) -3- pyrrolidinol (0.009mL, It 0.11mmol) handles and is stirred at room temperature 3 hours, then loading to SiO2(0.9g) and in SiO2(4g RediSep column) is enterprising Row chromatogram purification, is eluted with 0-15%MeOH/DCM, obtains 2- [[3,5- dicyano -4- ethyl -6- [(3R) -3- hydroxypyrroles Alkane -1- base] -2- pyridyl group] sulfanyl] -2- phenvl-acetamide (12mg, 70% yield) is white solid.LCMS m/z =408.1 [M+H]+。1H NMR (300MHz, DMSO-d6) δ ppm7.91 (br s, 1H), 7.57-7.48 (m, 2H), 7.43- 7.27 (m, 4H), 5.61 (s, 1H), 5.21-5.10 (m, 1H), 4.42 (br s, 1H), 4.01-3.72 (m, 4H), 2.74 (q, J =7.3Hz, 2H), 2.03-1.84 (m, 2H), 1.20 (t, J=7.6Hz, 3H).
Embodiment 161:
2- ((3,5- dicyano -4- ethyl -6- (2- oxa- -6- azaspiro [3.4] octyl- 6- yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides
The chloro- 4- ethyl -6- of step 1:2- (2- oxa- -6- azaspiro [3.4] octyl- 6- yl) pyridine -3,5- dimethoxy nitrile
At 0 DEG C, to chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (in 3 step 2 of embodiment describe synthesis, 680mg, 3mmol) and 2- oxa- -6- azaspiro [3.4] octane, oxalates (480mg, 1.5mmol) is at methylene chloride (20mL) In solution in Et is added3N (610mg, 6mmol).The mixture is stirred at room temperature overnight, is then diluted with EtOAc, then With water and salt water washing.The organic phase is post-processed, crude 2- chloro- 4- ethyl -6- (2- oxa- -6- azaspiro [3.4] is obtained Octyl- 6- yl) pyridine -3,5- dimethoxy nitrile (860mg), it is directly used in next step without being further purified.LCMS m/z= 303.0[M+H]+。
Step 2:2- ((3,5- dicyano -4- ethyl -6- (2- oxa- -6- azaspiro [3.4] octyl- 6- yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides
To the chloro- 4- ethyl -6- of crude 2- (2- oxa- -6- azaspiro [3.4] octyl- 6- yl) pyridine -3,5- dimethoxy nitrile KSAc (460mg, 4mmol) is added in the solution in n,N-Dimethylformamide (20mL) in (860mg).By the mixture in room Then K is added in room temperature in temperature stirring 2 hours2CO3(1.24g, 9mmol).The mixture is stirred at room temperature 2 hours, is then used The processing of methanesulfonic acid 2- amino -2- oxo -1- phenylethylester (describe synthesis in embodiment 3, step 5,2.06g, 9mmol).The mixture is stirred at room temperature overnight.Gained mixture is diluted with EtOAc (60mL) and with water (60mL) and salt Water (60mL) washing.Organic phase is post-processed, is then purified with Gradient chromatography using petroleum ether/EA (1/1-1/2), obtains 2- ((3,5- dicyano -4- ethyl -6- (2- oxa- -6- azaspiro [3.4] octyl- 6- yl) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine (200mg), is white solid.LCMS m/z=434.0 [M+H]+。1H NMR (400MHz, DMSO-d6)δppm 7.93 (s, 1H), 7.55-7.51 (m, 2H), 7.43-7.31 (m, 4H), 5.60 (s, 1H), 4.65-4.60 (m, 2H), 4.55-4.52 (m, 2H), 4.08-3.80 (m, 4H), 2.75 (q, J=6.0Hz, 2H), 2.27 (t, J=6.0Hz, 2H), 1.20 (t, J=6Hz, 3H)。
Embodiment 162:
(R) -2- ((3,5- dicyano -4- ethyl -6- (4- ethyl -1,4- Diazesuberane -1- base) pyridine -2- base) Amino) -2- phenyl-acetamides
By (2R) -2- [(the chloro- 3,5- dicyano -4- ethyl -2- pyridyl group of 6-) amino] -2- phenvl-acetamide (in reality Example 41 is applied, synthesis, 33mg, 0.10mmol are described in step 1) solution N- ethyl homopiperazine in THF (1mL) (0.04mL, 0.24mmol) is handled and is stirred at room temperature 19 hours, then loading to SiO2(0.9g) and in SiO2(4g RediSep column) on carry out chromatogram purification, with (the 5%NH of 0-15% gradient3MeOH solution)/DCM elution.The purifying is produced Object triturated under ether obtains (2R) -2- [[3,5- dicyano -4- ethyl -6- (4- ethyl-Isosorbide-5-Nitrae-Diazesuberane -1- base) - 2- pyridyl group] amino] -2- phenvl-acetamide (38mg, 91% yield) is white solid.LCMS m/z=432.4 [M+H ]+。1H NMR (300MHz, DMSO-d6) δ ppm 7.80 (s, 1H), 7.49-7.25 (m, 6H), 7.07 (d, J=5.9Hz, 1H), 5.43 (d, J=6.0Hz, 1H), 3.85-3.61 (m, 4H), 2.78-2.60 (m, 3H), 2.49-2.33 (m, 5H), 1.89-1.68 (m, 2H), 1.20 (t, J=7.5Hz, 3H), 0.93 (t, J=7.1Hz, 3H).
Embodiment 163:
(R) -2- ((3,5- dicyano -4- ethyl -6- (4- (3- (pyrrolidin-1-yl) propyl) -1,4- diaza cycloheptyl Alkane -1- base) pyridine -2- base) amino) -2- phenyl-acetamides
By (2R) -2- [(the chloro- 3,5- dicyano -4- ethyl -2- pyridyl group of 6-) amino] -2- phenvl-acetamide (in reality Example 41 is applied, synthesis, 23mg, 0.07mmol are described in step 1) and 1- (3- pyrrolidin-1-yl propyl)-Isosorbide-5-Nitrae-diaza cycloheptyl Mixture of the alkane (16mg, 0.08mmol) in THF (1mL) is handled with triethylamine (0.02mL, 0.15mmol) and to stir 18 small When.The mixture is diluted with DCM, loading to SiO2(1g), in purifying SiO2Chromatography is carried out on (4g RediSep column), uses 0- 40%MeOH, 0-2%NH3/ DCM elution, then uses Et2O grinding, obtains (2R) -2- [[3,5- dicyano -4- ethyl -6- [4- (3- pyrrolidin-1-yl propyl)-Isosorbide-5-Nitrae-Diazesuberane -1- base] -2- pyridyl group] amino] -2- phenvl-acetamide (26mg, 75% yield), it is white solid.LCMS m/z=515.4 [M+H]+。1H NMR (300MHz, DMSO-d6)δppm 7.86 (s, 1H), 7.53-7.25 (m, 6H), 7.08 (d, J=6.0Hz, 1H), 5.44 (d, J=6.0Hz, 1H), 3.89-3.61 (m, 6H), 2.93-2.55 (m, 10H), 2.42-2.34 (m, 2H), 1.87-1.69 (m, 6H), 1.66-1.53 (m, 2H), 1.20 (t, J =7.5Hz, 3H).
Embodiment 164:
2- (3,5- dicyano -4- cyclopropyl -6- (3- hydroxy piperidine -1- base) pyridine -2- base sulfenyl) -2- phenylacetyl Amine
Step 1:3- hydroxy piperidine -1- t-butyl formate
NaBH is added in the solution in methanol (25mL) to 3- oxo-piperidine -1- t-butyl formate (1g, 5mmol)4 (360mg, 10mmol).The reaction mixture is stirred 2 hours at 0 DEG C.The solvent under reduced pressure removes and the residue is dissolved in two Chloromethanes and filtering.The filtrate is concentrated to get 3- hydroxy piperidine -1- t-butyl formate (1g, 99%), is used in next step Without is further purified1H NMR (400MHz, CDCl3) δ ppm 3.81-3.70 (m, 2H), 3.60-3.51 (m, 1H), 3.18-3.02 (m, 2H), 1.95 (s, 1H), 1.91-1.86 (m, 1H), 1.82-1.72 (m, 1H), 1.59-1.42 (m, 11H).
The chloro- 4- cyclopropyl -6- of step 2:2- (3- hydroxy piperidine -1- base) pyridine -3,5- dimethoxy nitrile
3- hydroxy piperidine -1- t-butyl formate (1g, 5mmol) and HCl (2.0M in EtOAc, 5mL) are stirred in room temperature It mixes overnight.The solvent under reduced pressure removes.By residue saturation NaHCO3(aq) it neutralizes and is extracted with DCM.By organic layer salt Water washing, drying are simultaneously purified with column chromatography, are eluted, 0-10% with MeOH/DCM, obtain piperidin-3-ol (450mg).
To chloro- 4- cyclopropyl pyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (synthesis is described in embodiment 4, step 2, 236mg, 1mmol) be added in the solution in DMF (10mL) piperidin-3-ol (101mg, 1mmol) and triethylamine (0.14mL, 1mmol).The reaction mixture is stirred at room temperature 5 minutes.Water is added in the reaction mixture.The solid is filtered and is used in combination Column chromatography purifying, is eluted with petrol ether/ethyl acetate (0-33%), obtains the chloro- 4- cyclopropyl -6- of 2- (3- hydroxy piperidine -1- Base) pyridine -3,5- dimethoxy nitrile (210mg, 70%).LCMS m/z=303.0 [M+H]+。
Step 3:2- (3,5- dicyano -4- cyclopropyl -6- (3- hydroxy piperidine -1- base) pyridine -2- base sulfenyl) -2- benzene Yl acetamide
By thioacetic acid potassium (95mg, 0.83mmol) and the chloro- 4- cyclopropyl -6- of 2- (3- hydroxy piperidine -1- base) pyridine - Solution of 3, the 5- dimethoxy nitriles (210mg, 0.7mmol) in n,N-Dimethylformamide (DMF) (7mL) is stirred at room temperature 30 points Clock.Then be added methanesulfonic acid 2- amino -2- oxo -1- phenylethylester (synthesis is described in embodiment 3, step 5, 191mg, 0.83mmol) and triethylamine (0.19mL, 1.4mmol).The reaction mixture is stirred at room temperature overnight.Water is added to In the reaction mixture.The solid is filtered and is purified with column chromatography, is eluted with DCM/MeOH (0-5%), obtains 2- (3,5- bis- Cyano -4- cyclopropyl -6- (3- hydroxy piperidine -1- base) pyridine -2- base sulfenyl) -2- phenyl-acetamides (110mg, 36%).LCMS M/z=433.9 [M+H]+。1H NMR (400MHz, CDCl3) δ ppm 7.48-7.43 (m, 2H), 7.42-7.33 (m, 3H), 6.91-6.80 (m, 1H), 5.80-5.65 (m, 1H), 5.29-5.20 (m, 1H), 4.64-4.45 (m, 1H), 4.04-3.98 (m, 0.5H), 3.94-3.87 (m, 1.5H), 3.81-3.75 (m, 0.5H), 3.65-3.56 (m, 0.5H), 3.48-3.39 (m, 0.5H), 3.07-2.98 (m, 0.5H), 2.32 (br s, 1H), 2.12-1.88 (m, 3H), 1.79-1.69 (m, 0.5H), 1.64- 1.49 (m, 1.5H), 1.33-1.24 (m, 2H), 1.21-1.06 (m, 2H).
Embodiment 165
2- ((the chloro- 4- ethyl -6- of 3,5- bis- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides
The chloro- 4- ethyl -2,6- difluoro pyridine of step 1:3,5- bis-
By 3,5- bis- chloro- 2,4,6- trifluoromethyl pyridines (2.32g, 11.49mmol) are dissolved in tetrahydrofuran (18mL) and cooling To -78 DEG C.Ethylmagnesium chloride (6.32mL, 12.64mmol) is added dropwise in the solution of merging and after 20 minutes, by the reaction It is quenched with saturated water sodium bicarbonate aqueous solution.The reaction is diluted with EtOAc, forms lotion sample mixture.Be added HCl until PH~6 also smash the lotion and form solution.It is extracted with EtOAc (3x) and by combined organic matter MgSO4It is dry, mistake It filters and is concentrated, obtain chloro- 4- ethyl -2, the 6- difluoro pyridine (1.76g, 8.3mmol) of 3,5- bis-.LCMS m/z=211.9 [M+H ]+。
Step 2:2- ((the chloro- 4- ethyl -6- fluorine pyridine -2- base of 3,5- bis-) sulfenyl) -2- phenyl-acetamides
Thioacetic acid S- (2- amino -2- oxo -1- phenylethyl) ester (in 62 step 5 of embodiment is described into conjunction At 401mg, 1.916mmol) and NaBH4(75mg, 1.982mmol) is added in bottle and is suspended in ethyl alcohol (30mL). The mixture is heated to 60 DEG C and continues 5 minutes (bubbling/gas release stops).By the chloro- 4- ethyl -2,6- difluoro pyrrole of 3,5- bis- Solution of the pyridine (346mg, 1.632mmol) in EtOH (15mL) adds to the mixture and the material is stirred at room temperature 15 points Clock.The mixture is concentrated, Et is used2O/ heptane grinds and filters out colloid and the filtrate is concentrated, and obtaining 2-, ((3,5- bis- is chloro- 4- ethyl -6- fluorine pyridine -2- base) sulfenyl) -2- phenyl-acetamides (445mg, 1.078mmol, 66% yield).LCMS m/z= 359.0[M+H]+。
Step 3:2- ((the chloro- 4- ethyl -6- of 3,5- bis- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides
By 2- ((3,5- bis- chloro- 4- ethyl -6- fluorine pyridine -2- base) sulfenyl) -2- phenyl-acetamides (440mg, 1.225mmol) adds in bottle with 1- methyl-1,4- Diazesuberane (0.228mL, 1.837mmol) and be suspended in tetrahydro Furans (12mL).The mixture is flowed back 16 hours at 80 DEG C, is then reheated 8 hours at 100 DEG C.Brown solid is precipitated, it will It is filtered out.The material is purified into (40g column on silica gel；EtOAc to 3:1EtOAc:EtOH w/1.5%NH4OH).By institute It needs fraction to merge and be concentrated, obtains 2- ((3,5- bis- chloro- 4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyrroles Pyridine -2- base) sulfenyl) -2- phenyl-acetamides (160mg, 0.353mmol, 29% yield) are pale solid.LCMS m/z =453.1 [M+H]+。1H NMR (400MHz, chloroform-d) δ ppm 7.44-7.51 (m, 2H) 7.31-7.43 (m, 3H) 6.80 (br.s., 1H) 5.66 (br.s., 1H) 5.45 (s, 1H) 3.54-3.78 (m, 4H) 2.92 (q, J=7.58Hz, 2H) 2.81- 2.87 (m, 2H) 2.60-2.77 (m, 2H) 2.43 (s, 3H) 1.96-2.15 (m, 2H) 1.18 (t, J=7.58Hz, 3H).
Embodiment 166:
2- ((3,5- dicyano -6- (1,1- sulfur dioxide morpholino) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide
To 2- [(the bromo- 3,5- dicyano -4- ethyl -2- pyridyl group of 6-) sulfanyl] -2- phenvl-acetamide (in embodiment 6, synthesis, 30mg, 0.07mmol are described in step 1) and mixing of the triethylamine (0.02mL, 0.16mmol) in THF (2mL) Thiomorpholine dioxide (11mg, 0.08mmol) is added in object.The reaction mixture is stirred at room temperature 17 hours.Water is added (5mL) and the mixture is stirred 30 minutes, filters and washed with water (3x 10mL).Attempt viscous solid being dissolved in EtOAc, White fluffy solid is formed, it is dried in vacuo at 50 DEG C, obtains 2- [[3,5- dicyano -6- (1,1- dioxo-Isosorbide-5-Nitrae-thiophene Piperazine -4- base) -4- ethyl -2- pyridyl group] sulfanyl] -2- phenvl-acetamide (8mg, 23% yield) is white powder. LCMS m/z=454.2 [M-H]-.1H NMR (300MHz, DMSO-d6, D2O exchange) δ ppm 7.50-7.28 (m, 5H), 5.47 (s, 1H), 4.32-4.27 (m, 2H), 4.20-4.11 (m, 2H), 3.35-3.18 (m, 4H), 2.76 (q, J=7.4Hz, 2H), 1.17 (t, J=7.6Hz, 3H).
Embodiment 167:
2- ((3,5- dicyano -4- ethyl -6- (methyl (2- (piperazine -1- base) ethyl) amino) pyridine -2- base) sulphur Base) -2- phenyl-acetamides
Step 1:4- (2- (((benzyl oxygroup) carbonyl) (methyl) amino) ethyl) piperazine -1- t-butyl formate
To piperazine -1- t-butyl formate (558mg, 3.00mmol) and methyl (2- oxoethyl) benzyq carbamate (621mg, 3.00mmol) in the solution in methylene chloride (DCM) (30mL) be added sodium triacetoxy borohydride (1270mg, 5.99mmol).The reaction mixture is stirred at room temperature overnight.The reaction is diluted with DCM and uses saturation NaHCO3Solution is washed It washs.Organic layer is dry, it is concentrated and is purified with column chromatography, eluted with EtOAc- hexane (0-33%), obtain 4- (2- (((benzyl Oxygroup) carbonyl) (methyl) amino) ethyl) piperazine -1- t-butyl formate (950mg, 84%).LCMS m/z=378.0 [M+H ]+。
Step 2:4- (2- (methylamino) ethyl) piperazine -1- t-butyl formate
To 4- (2- (((benzyl oxygroup) carbonyl) (methyl) amino) ethyl) piperazine -1- t-butyl formate (950mg, Palladium/carbon (10%, 27mg, 10mol%) 2.52mmol) is added in the solution in methanol (25mL).The reaction mixture is existed It is stirred overnight under room temperature nitrogen atmosphere.The mixture is filtered and the filtrate is concentrated to get 4- (2- (methylamino) ethyl) piperazine Piperazine -1- t-butyl formate (490mg, 80%), is yellow oil.1H NMR (400MHz, CDCl3) δ ppm 3.48-3.42 (m, 4H), 2.72 (t, J=6.0Hz, 2H), 2.53 (t, J=6.1Hz, 2H), 2.48 (d, J=5.9Hz, 3H), 2.44-2.38 (m, 4H), 1.48 (s, 9H).
Step 3:4- (2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) (methyl) amino) ethyl) piperazine -1- t-butyl formate
To chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in embodiment 3, step 2,455mg, 4- (2- (methylamino) ethyl) piperazine -1- t-butyl formate 2.01mmol) is added in the solution in DMF (20mL) (490mg, 2.01mmol) and triethylamine (0.281mL, 2.01mmol).The reaction mixture is stirred at room temperature 30 minutes.It will Water adds in the reaction.The solid is filtered and is dried to obtain 4- (2- ((the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) (methyl) amino) ethyl) piperazine -1- t-butyl formate (640mg).
By thioacetic acid potassium (203mg, 1.77mmol) and 4- (2- ((chloro- 3, the 5- dicyano -4- ethylpyridine -2- of 6- Base) (methyl) amino) ethyl) piperazine -1- t-butyl formate (640mg, 1.48mmol) is at n,N-Dimethylformamide (15mL) In solution be stirred at room temperature 30 minutes.Then be added methanesulfonic acid 2- amino -2- oxo -1- phenylethylester (in embodiment 3, Synthesis, 407mg, 1.77mmol are described in step 5) and triethylamine (0.41mL, 2.96mmol).By the reaction mixture in room Temperature is stirred overnight.Water is added in the reaction.The solid is filtered and is purified with column chromatography, is eluted with MeOH/DCM (0-5%), Obtain 4- (2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (first Base) amino) ethyl) piperazine -1- t-butyl formate (450mg, 54%).LCMS m/z=564.3 [M+H]+。
Step 4:2- ((3,5- dicyano -4- ethyl -6- (methyl (2- (piperazine -1- base) ethyl) amino) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides
To 4- (2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) (methyl) amino) ethyl) piperazine -1- t-butyl formate (450mg, 0.80mmol) is in the solution in methylene chloride (5mL) It is added trifluoroacetic acid (0.12mL, 1.60mmol).The reaction mixture is stirred at room temperature overnight.The solvent is removed and should Residue is redissolved with water, with saturation NaHCO3Solution neutralizes, and is extracted with DCM.Organic layer is concentrated and is purified with column chromatography, is used MeOH/DCM (0-20%) elution, obtains 2- ((3,5- dicyano -4- ethyl -6- (methyl (2- (piperazine -1- base) ethyl) ammonia Base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides (236mg, 64%).LCMS m/z=464.2 [M+H]+。1H NMR (400MHz, CDCl3) δ ppm 7.48-7.42 (m, 2H), 7.41-7.32 (m, 3H), 7.23 (br s, 1H), 5.80 (br s, 1H), 5.40 (s, 1H), 4.17-4.08 (m, 1H), 3.76-3.66 (m, 1H), 3.45 (s, 3H), 2.98-2.83 (m, 6H), 2.80-2.72 (m, 1H), 2.71-2.63 (m, 1H), 2.61-2.50 (s, 4H), 2.40 (br s, 1H), 1.32 (t, J= 7.6Hz, 3H).
Embodiment 168:
(R) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides
Step 1:(S) the chloro- 4- ethyl -6- of -2- (3- hydroxyl pyrrolidine -1- base) pyridine -3,5- dimethoxy nitrile
In room temperature, to chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (such as embodiment 3, described in step 2,678mg, 3.00mmol) and (S)-pyrrolidines -3- alcohol (261mg, 3.00mmol) is in the solution in n,N-Dimethylformamide (20mL) It is added triethylamine (0.418mL, 3.00mmol), gained mixture is stirred at room temperature 1 hour.The reaction mixture is poured into water It is extracted in (100mL) and with EtOAc (100mL x 2).Combined organic layer is dried and concentrated, the chloro- 4- second of (S) -2- is obtained Base -6- (3- hydroxyl pyrrolidine -1- base) pyridine -3,5- dimethoxy nitrile (620mg, 75% yield), is pale solid.LCMS m/z =276.9 [M+H]+。
Step 2:2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides
By the chloro- 4- ethyl -6- of (S) -2- (3- hydroxyl pyrrolidine -1- base) pyridine -3,5- dimethoxy nitrile (500mg, 1.81mmol), solution of the thioacetic acid potassium (248mg, 2.17mmol) in n,N-Dimethylformamide (DMF) (15mL) is in room Temperature stirring 30 minutes, then (describes conjunction for methanesulfonic acid 2- amino -2- oxo -1- phenylethylester in embodiment 3, step 5 The solution is added at 497mg, 2.17mmol) and triethylamine (0.50mL, 3.6mmol).The reaction mixture is stirred at room temperature 12 hours.The reaction mixture is extracted down in water (100mL) and with EtOAc (100mL x 2).Combined organic layer is done It is dry, it is concentrated and (is eluted with MeOH/DCM 0-2%) with silica gel column purification, obtain 2- ((3,5- dicyano -4- ethyl -6- ((S) - 3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides (380mg, 51% yield) are white solid. LCMS m/z=407.9 [M+H]+。
Step 3:(R) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides
By 2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- With chirality HPLC separation, (chiralpak-IC column, HEX-EtOH (FA), obtains (R)-to phenyl-acetamides (250mg, 0.62mmol) 2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides. The absolute configuration of the chiral centre adjacent with sulphur is analyzed by VCD confirms (30mg).LCMS m/z=408.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.91 (br s, 1H), 7.52 (vbr s, 1H), 7.52-7.49 (m, 1H), 7.44-7.22 (m, 4H), 5.61 (s, 1H), 5.14 (d, J=3.4Hz, 1H), 4.41 (s, 1H), 4.05-3.65 (m, 4H), 2.74 (q, J= 7.4Hz, 2H), 2.07-1.85 (m, 2H), 1.21 (q, J=7.6Hz, 3H).
Embodiment 170:
2- ((6- ((2- (4- (amino methyl) -4- hydroxy piperidine -1- base) ethyl) (methyl) amino) -3,5- dicyano - 4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides
Step 1:((4- hydroxyl -1- (2- (methylamino) ethyl) piperidin-4-yl) methyl) t-butyl carbamate
To ((4- hydroxy piperidine -4- base) methyl) t-butyl carbamate (320mg, 1.39mmol) and methyl (2- oxo Ethyl) triacetoxy borohydride hydrogen is added in benzyq carbamate (288mg, 1.39mmol) in the solution in methylene chloride (14mL) Change sodium (589mg, 2.78mmol).The reaction mixture is stirred at room temperature overnight, then diluted with DCM and uses saturation NaHCO3 Solution washing.Organic layer is dry, it is concentrated and (is eluted with petroleum ether/EtOAc, 3:1) with flash column chromatography, obtained 400mg residue.The residue is dissolved in methanol (10mL) and palladium/carbon (10%, 10mg, 0.1mmol) is added.The reaction is mixed Object is closed in room temperature H2It is stirred overnight under atmosphere.The mixture is filtered and the filtrate is concentrated, obtains ((4- hydroxyl -1- (2- (first Base amino) ethyl) piperidin-4-yl) methyl) t-butyl carbamate (270mg, 0.939mmol, 68% yield).1H NMR (400MHz, CDCl3) δ ppm 5.07 (br.s, 1H), 3.19-3.10 (m, 2H), 2.71 (t, J=6.1Hz, 2H), 2.66- 2.58 (m, 2H), 2.56-2.50 (m, 2H), 2.46 (s, 3H), 2.44-2.36 (m, 2H), 1.69-1.57 (m, 4H), 1.45 (s, 9H).1 proton does not observe.
Step 2:((1- (2- ((the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) (methyl) amino) ethyl) -4- hydroxyl Phenylpiperidines -4- base) methyl) t-butyl carbamate
To chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in embodiment 3, step 2,212mg, ((4- hydroxyl -1- (2- (methylamino) ethyl) 0.94mmol) is added in the solution in N,N-dimethylformamide (10mL) Piperidin-4-yl) methyl) t-butyl carbamate (270mg, 0.94mmol) and triethylamine (0.13mL, 0.94mmol).This is anti- Mixture is answered to be stirred at room temperature 30 minutes.Water is added in the reaction mixture and the solid is filtered and uses flash column chromatography pure Change (being eluted with DCM/MeOH, 20:1), obtains ((1- (2- ((chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-) (methyl) ammonia Base) ethyl) -4- hydroxy piperidine -4- base) methyl) t-butyl carbamate (300mg, 67% yield).LCMS m/z=477.2 [M+H]+。1H NMR (400MHz, CDCl3) δ ppm4.95 (s, 1H), 3.92 (t, J=6.3Hz, 2H), 3.47 (s, 3H), 3.19- 3.11 (m, 2H), 2.98 (q, J=7.6Hz, 2H), 2.83-2.48 (m, 6H), 1.71-1.56 (m, 4H), 1.46 (s, 9H), 1.36 (t, J=7.6Hz, 3H).Two protons do not observe.
Step 3:((1- (2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl Pyridine -2- base) (methyl) amino) ethyl) -4- hydroxy piperidine -4- base) methyl) t-butyl carbamate
By ((1- (2- ((the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) (methyl) amino) ethyl) -4- hydroxyl piperazine Pyridine -4- base) methyl) t-butyl carbamate (0.413mL, 0.63mmol) and thioacetic acid potassium (86mg, 0.76mmol) in N, Solution in dinethylformamide (6mL) is stirred at room temperature 30 minutes.By triethylamine (0.175mL, 1.26mmol) and methylsulphur Sour 2- amino -2- oxo -1- phenylethylester (synthesis, 173mg, 0.76mmol are described in embodiment 3, step 5) adds to The reaction.The reaction mixture is stirred overnight at 25 DEG C.Water is added and the solid is filtered and flash column chromatography is used (to use DCM/MeOH, 20:1 elution), obtain ((1- (2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyan Base -4- ethylpyridine -2- base) (methyl) amino) ethyl) -4- hydroxy piperidine -4- base) methyl) t-butyl carbamate (250mg, 65% yield).1H NMR (400MHz, CDCl3) δ ppm 7.48 (d, J=6.0Hz, 2H), 7.45-7.35 (m, 3H), 5.82 (s, 1H), 5.46 (s, 1H), 4.93 (s, 1H), 4.31-4.20 (m, 1H), 3.81-3.67 (m, 1H), 3.47 (s, 3H), 3.18-3.09 (m, 2H), 2.93 (q, J=7.6Hz, 2H), 2.90-2.51 (m, 6H), 1.70-1.53 (m, 5H), 1.46 (s, 9H), 1.33 (t, J=7.6Hz, 3H).1 proton does not observe.
Step 4:2- ((6- ((2- (4- (amino methyl) -4- hydroxy piperidine -1- base) ethyl) (methyl) amino) -3,5- Dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides
To ((1- (2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) (methyl) amino) ethyl) -4- hydroxy piperidine -4- base) methyl) t-butyl carbamate (250mg, 0.41mmol) is two Trifluoroacetic acid (0.06mL, 0.8mmol) is added in solution in chloromethanes (5mL).The reaction mixture was stirred at room temperature Night.The solvent is removed and is redissolved the residue with water, with saturation NaHCO3Solution is neutralized and is extracted with DCM.It will be organic Layer is dry, is concentrated and (is eluted with DCM/MeOH, 5:1) with flash column chromatography, obtains 2- ((6- ((2- (4- (amino first Base) -4- hydroxy piperidine -1- base) ethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl Acetamide (122mg, 59%).LCMS m/z=508.3 [M+H]+。1H NMR (400MHz, CDCl3) δ ppm 7.62 (br s, 1H), 7.49-7.42 (m, 2H), 7.42-7.31 (m, 3H), 5.62 (br s, 1H), 5.40 (s, 1H), 4.28-4.19 (m, 1H), 3.67-3.57 (m, 1H), 3.46 (s, 3H), 2.91 (q, J=7.6Hz, 2H), 2.86-2.80 (m, 1H), 2.78-2.65 (m, 3H), 2.62-2.45 (m, 4H), 1.65 (br s, 3H), 1.56-1.50 (m, 2H), 1.45-1.36 (m, 2H), 1.31 (t, J= 7.6Hz, 3H).
Embodiment 171
2- ((4- cyano -3- (1,4- Diazesuberane -1- base) -6,7- dihydro -5H- cyclopenta [c] pyridine - 1- yl) sulfenyl) -2- phenyl-acetamides
Chloro- 6,7- dihydro -5H- cyclopenta [c] pyridine -4- formonitrile HCN of step 1:1,3- bis-
2- oxo-cyclopentane Ethyl formate (3.90g, 25.00mmol) is dissolved in methanol (20mL) and 2- cyano second is added Amide (2.102g, 25mmol) and KOH (1.473g, 26.3mmol) flow back the reaction 18 hours.It is after 18 hours, this is anti- It should cool down and white solid is filtered out and is washed with methanol.Methanol suction is fallen, the residue of 2.78g is obtained.By 1g remnants Object is placed in big microwave vial and benzyltrimethylammonium chloride (3.16g, 17.03mmol) is added.Then it is added dropwise while stirring POCl3(10.58ml, 114mmol) (observes bubbling and heat release).By bottle seal and 165 DEG C microwave heating 5.5 hours. It is cooled to room temperature, which is added slowly to ice/water/DCM.It separates each layer and washes twice water layer with DCM.By having for merging Machine object is washed with sodium sulphate, and DCM is evaporated in filtering.(24g column, the hexane with 0-25% ethyl acetate are molten for normal phase silica gel chromatography purifying Liquid elution), obtain chloro- 6,7- dihydro -5H- cyclopenta [c] pyridine -4- formonitrile HCN of 1,3- bis- (0.650g, 3.05mmol, 54% yield).LCMS m/z=212.8 [M+H]+。
Step 2:2- ((chloro- 4- cyano -6,7- dihydro -5H- cyclopenta [c] pyridine -1- base of 3-) sulfenyl) -2- benzene Yl acetamide
Thioacetic acid S- (2- amino -2- oxo -1- phenylethyl) ester (in 62 step 5 of embodiment is described into conjunction Be dissolved in 15ml ethyl alcohol at 216mg, 1.033mmol) and be added portionwise at 65 DEG C sodium borohydride (46.2mg, 1.22mmol) and The temperature stirs 15 minutes.The mixture is removed into heating source, simultaneously chloro- 6, the 7- dihydro -5H- cyclopentadiene of 1,3- bis- is added in cooling And [c] pyridine -4- formonitrile HCN (200mg, 0.939mmol) and again by the reaction 75 DEG C heat 3 minutes.The reaction is condensed into Solid obtains 2- ((the chloro- 4- cyanogen of 3- by it in 12g purified on silica column (with the hexanes of 15-70% ethyl acetate) Base -6,7- dihydro -5H- cyclopenta [c] pyridine -1- base) sulfenyl) -2- phenyl-acetamides (182mg, 0.529mmol, 56% Yield).LCMS m/z=343.9 [M+H]+。
Step 3:2- ((4- cyano -3- (1,4- Diazesuberane -1- base) -6,7- dihydro -5H- cyclopenta [c] Pyridine -1- base) sulfenyl) -2- phenyl-acetamides
By 2- ((chloro- 4- cyano -6,7- dihydro -5H- cyclopenta [c] pyridine -1- base of 3-) sulfenyl) -2- phenyl second Amide (180mg, 0.524mmol) is dissolved in Isosorbide-5-Nitrae-dioxanes (20mL) and Isosorbide-5-Nitrae-Diazesuberane base -1- formic acid uncle is added Butyl ester (189mg, 0.942mmol) and DIEA (0.091mL, 0.524mmol).The microwave vial is closed the lid and at 120 DEG C It heats 48 hours in heating plate, stirs simultaneously.The dioxanes is evaporated and the thick material is dissolved in DCM and on 12g silicagel column Purifying, with the hexanes of 12-70% ethyl acetate, obtains 4- (1- ((2- amino -2- oxo -1- phenylethyl) sulphur Base) -4- cyano -6,7- dihydro -5H- cyclopenta [c] pyridin-3-yl) -1,4- Diazesuberane -1- t-butyl formate (120mg) LCMS m/z=508.4 [M+H]+.The product is handled 1 hour with DCM/TFA1:1 in room temperature.The solvent is evaporated And filter the residue under a high vacuum, solid is obtained, water is dissolved in, is neutralized with excessive saturated sodium bicarbonate aqueous solution And be extracted into DCM, obtain 2- ((4- cyano -3- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -6,7- dihydro -5H- cyclopenta [c] pyridine -1- base) sulfenyl) -2- phenyl-acetamides (80mg, 0.196mmol, 38% yield).LCMS m/z=408.1 [M+H ]+。1H NMR (400MHz, DMSO-d6) δ ppm 1.74-1.92 (m, 2H) 1.99-2.17 (m, 2H) 2.57-2.71 (m, 2H) 2.77 (t, J=5.45Hz, 2H) 2.83-3.00 (m, 4H) 3.74-3.93 (m, 4H) 6-5.52 (s, 1H) 7.19-7.43 (m, 4H) 7.44-7.54 (m, 2H) 7.85 (s, 1H) 8.3 (s, 1H).
Embodiment 172
2- ((6- (4- (1H- imidazoles -1- base) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides
Step 1:2- (4- (1H- imidazoles -1- base) piperidin-1-yl) -4- ethyl -6- mercaptopyridine -3,5- dimethoxy nitrile
4- (1H- imidazoles -1- base) piperidines (343mg, 2.27mmol) is dissolved in DCM (5mL) and is added the mixture to 2,6- bis- chloro- 4- ethylpyridine -3,5- dimethoxy nitriles (describing synthesis, 0.513g, 2.270mmol in 3 step 2 of embodiment) and In triethylamine (0.230g, 2.270mmol).The mixture is stirred at room temperature 12 hours.The mixture is diluted with DCM, is used Salt water washing, is dried and concentrated, and obtains 2- (4- (1H- imidazoles -1- base) piperidin-1-yl) chloro- 4- ethylpyridine -3,5- bis- of -6- Formonitrile HCN (380mg).The crude product and thioacetic acid potassium (259mg, 2.27mmol) are added into n,N-Dimethylformamide (10mL) And the mixture is stirred 4 hours at 25 DEG C.The mixture is adjusted to pH 5 with 1N HCl, is used in combination with water (30mL) dilution DCM (30mL x 3) extraction.Organic layer is dried and concentrated to obtain 2- (4- (1H- imidazoles -1- base) piperidines -1- with sodium sulphate Base) -4- ethyl -6- mercaptopyridine -3,5- dimethoxy nitrile (220mg, 29% yield).LCMS m/z=339.1 [M+H]+。
Step 2:2- ((6- (4- (1H- imidazoles -1- base) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base) Sulfenyl) -2- phenyl-acetamides
By 2- (4- (1H- imidazoles -1- base) piperidin-1-yl) -4- ethyl -6- mercaptopyridine -3,5- dimethoxy nitrile (180mg, 0.532mmol), methanesulfonic acid 2- amino -2- oxo -1- phenylethylester (244mg, 1.064mmol) and potassium carbonate (73.5mg, It 0.532mmol) adds in N,N-dimethylformamide (10mL).The mixture is stirred 4 hours at 40 DEG C.Then by water (20mL) is added in the mixture and is extracted gained mixture DCM (30mL x 3).By combined organic layer sodium sulphate Dry, then residue preparative-HPLC is purified, obtains 2- ((6- (4- (1H- imidazoles -1- base) piperidines -1- by concentration Base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides (20mg, 8% yield).LCMS m/z= 471.7[M+H]+。1H NMR (400MHz, MeOD) δ ppm8.26 (s, 1H), 8.11 (s, 1H), 7.65-7.50 (m, 2H), 7.46- 7.32 (m, 3H), 7.16 (s, 1H), 5.54 (s, 1H), 4.87 (m, 2H), 4.63-4.48 (m, 1H), 3.47-3.29 (m, 2H), 2.94 (q, J=7.6Hz, 2H), 2.27 (d, J=12.4Hz, 2H), 2.08 (tt, J=12.7,6.3Hz, 2H), 1.33 (t, J= 7.6Hz, 3H).
Embodiment 173:
2- ((3,5- dicyano -4- ethyl -6- (4- (pyridin-4-yl methyl) piperazine -1- base) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides
Step 1:4- (pyridin-4-yl methyl) piperazine -1- t-butyl formate
Potassium carbonate is added in the solution in acetonitrile (10mL) to 4- (bromomethyl) pyridine (300mg, 1.74mmol) Then piperazine -1- t-butyl formate (325mg, 1.74mmol) is added in (362mg, 2.62mmol).The mixture is stirred in room temperature It mixes overnight.Then EtOAc and H is added2O.It separates each layer and extracts water layer with EtOAc.Combined organic phase is washed with salt It washs, uses Na2SO4It is dried and concentrated, obtains 4- (pyridin-4-yl methyl) piperazine -1- t-butyl formate (378mg).LCMS m/z= 278.1[M+H]+。
Step 2:1- (pyridin-4-yl methyl) piperazine
By 4- (pyridin-4-yl methyl) piperazine -1- t-butyl formate (332mg, 1.20mmol) in 3.0mL methylene chloride It is stirred overnight with the solution in 3.0mL trifluoroacetic acid in environment temperature.All volatile matters are removed in vacuum, 1- (pyridine-is obtained 4- ylmethyl) piperazine (212mg), it is used in next step without purification.LCMS m/z=177.9 [M+H]+。
The chloro- 4- ethyl -6- of step 3:2- (4- (pyridin-4-yl methyl) piperazine -1- base) pyridine -3,5- dimethoxy nitrile
Triethylamine is added in the solution in acetonitrile (10.0mL) to 1- (pyridin-4-yl methyl) piperazine (180mg) (0.637mL, 4.57mmol) is then added chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- and (retouches in embodiment 3, step 2 Synthesis, 230mg, 1.02mmol are stated).The reaction is stirred at room temperature 3 hours.The mixture is poured into 20mL water.By institute Solution is obtained to be extracted with 3x 20mL ethyl acetate.Organic layer is merged, with aqueous sodium carbonate and salt water washing, dry and vacuum Concentration, obtains raw product, is yellow oil.The residue is placed on silicagel column and with ethyl acetate/hexane (1:2-1:0) Elution, obtain the chloro- 4- ethyl -6- of 2- (4- (pyridin-4-yl methyl) piperazine -1- base) pyridine -3,5- dimethoxy nitrile (166mg, 0.45mmol).LCMS m/z=366.7 [M+H]+。
Step 4:2- ((3,5- dicyano -4- ethyl -6- (4- (pyridin-4-yl methyl) piperazine -1- base) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides
Thioacetic acid potassium (60mg, 0.52mmol) is added into the chloro- 4- ethyl -6- of 2- (4- (pyridin-4-yl methyl) piperazine - 1- yl) pyridine -3,5- dimethoxy nitrile (160mg, 0.44mmol) is in the solution in n,N-Dimethylformamide (5.0mL).30 points Zhong Hou, by methanesulfonic acid 2- amino -2- oxo -1- phenylethylester (describe synthesis in embodiment 3, step 5,100mg, It 0.44mmol) adds in the reaction mixture, triethylamine (0.122mL, 0.872mmol) then is added.By the reaction mixture It is stirred at room temperature overnight.Water is added in the reaction and filters the solid of formation.Then the solid is pure with preparative-HPLC Change, obtains 2- ((3,5- dicyano -4- ethyl -6- (4- (pyridin-4-yl methyl) piperazine -1- base) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides (30mg, 0.059mmol, 14% yield), are yellow solid.LCMS m/z=497.7 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.54 (d, J=5.7Hz, 2H), 7.90 (s, 1H), 7.48 (d, J=6.7Hz, 2H), 7.41- 7.30 (m, 5H), 5.50 (s, 1H), 3.90 (s, 4H), 3.60 (s, 2H), 2.79-2.71 (m, 2H), 1.21-1.16 (m, 6.7Hz, 3H).5H is not observed.
Embodiment 174:
2- ((3,5- dicyano -6- (2- (dimethylamino) ethyoxyl) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl Acetamide
The chloro- 6- of step 1:2- (2- (dimethylamino) ethyoxyl) -4- ethylpyridine -3,5- dimethoxy nitrile
To chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in embodiment 3, step 2,300mg, 1.33mmol) and triethylamine is added in the solution in acetonitrile (10mL) in 2- (dimethylamino) ethyl alcohol (118mg, 1.33mmol) (0.185mL, 1.32mmol), by the reaction mixture 20 DEG C stirred under nitrogen 3 hours.The reaction mixture is evaporated and incited somebody to action The residue is allocated between ethyl acetate (100mL) and water (50mL).The organic phase is washed with water (50mL), uses sodium sulphate It dries, filters and is evaporated in vacuo, obtain the chloro- 6- of raw product 2- (2- (dimethylamino) ethyoxyl) -4- ethylpyridine -3,5- Dimethoxy nitrile (300mg), is brown oil.LCMS m/z=279.1 [M+H]+。
Step 2:2- ((3,5- dicyano -6- (2- (dimethylamino) ethyoxyl) -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides
By the chloro- 6- of 2- (2- (dimethylamino) ethyoxyl) -4- ethylpyridine -3,5- dimethoxy nitrile (300mg, 1.08mmol), thioacetic acid potassium (148mg, 1.29mmol) and triethylamine (0.450mL, 3.2mmol) are in N, N- dimethyl formyl Solution in amine (20mL) 20 DEG C stirred under nitrogen 2 hours.Then methanesulfonic acid 2- amino -2- oxo -1- phenylethyl is added Ester (describes synthesis, 247mg, 1.08mmol) in embodiment 3, step 5.The reaction mixture is stirred at room temperature 3 hours. The reaction mixture is cooled to room temperature and is allocated between methylene chloride (50mL) and water (50mL).By the organic phase water (50mL) washing with sodium sulphate drying and is evaporated in vacuo, obtains the crude product.The crude product purified by silica gel column purification (is used CH2Cl2/ MeOH, 20:1 elution), obtain 2- ((3,5- dicyano -6- (2- (dimethylamino) ethyoxyl) -4- ethylpyridine - 2- yl) sulfenyl) -2- phenyl-acetamides (50mg) are white solid.LCMS m/z=410.1 [M+H]+。1H NMR (400MHz, DMSO-d6+D2O) δ ppm 7.54-7.52 (m, 2H), 7.44-7.38 (m, 3H), 5.62 (s, 1H), 4.92-4.79 (m, 2H), 3.60-3.55 (m, 2H), 2.90-2.84 (m, 8H), 1.23 (t, J=7.6Hz, 3H).
Embodiment 175
2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine -2- Base) piperidines -3- base) amino) acetic acid
To 2- ((6- (3- amino piperidine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- phenyl Acetamide (synthesis, 500mg, 1.156mmol are described in embodiment 25, step 2) is added in the solution in DMF (5mL) 2- bromo-acetic acid tert-butyl (225mg, 1.156mmol) and potassium carbonate (320mg, 2.312mmol).The mixture is stirred at 70 DEG C Overnight.The reaction mixture is concentrated.The residue is added into silicagel column and is eluted with hexane/EtOAc (1:1), 2- is obtained ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine -2- base) piperidines -3- Base) amino) tert-butyl acetate (500mg, 79% yield).To 2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulphur Base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) piperidines -3- base) amino) tert-butyl acetate (500mg, 0.915mmol) exists 2,2,2- trifluoroacetic acids (521mg, 4.57mmol) are added in solution in methylene chloride (100mL).The reaction mixture is existed 25 DEG C are stirred overnight.The reaction mixture is concentrated, then residue preparative-HPLC is purified, obtains 2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine -2- base) piperidines -3- base) amino) Two kinds of unknown diastereoisomers (diastereoisomer 2,45mg) of acetic acid.1H NMR (400MHz, DMSO-d6)δppm 9.22 (s, 2H), 7.96 (s, 1H), 7.55-7.36 (m, 6H), 5.50 (s, 1H), 4.59 (d, J=9.7Hz, 1H), 4.33 (d, J =13.3Hz, 1H), 4.02 (s, 2H), 3.39-3.19 (m, 2H), 3.17 (t, J=11.2Hz, 1H), 2.25-2.10 (m, 2H), 1.90 (d, J=12.9Hz, 1H), 1.72-1.55 (m, 2H), 1.17 (d, J=8.8Hz, 2H), 1.04-0.94 (m, 2H).LCMS M/z=491.1 [M+H]+。
Embodiment 176
2- ((3,5- dicyano -4- ethyl -6- (4- (oxazole -2- ylmethyl) piperazine -1- base) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides
Step 1:4- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) piperazine -1- t-butyl formate
By chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in embodiment 3, step 2,4.0g, It 17.69mmol) is dissolved in tetrahydrofuran (50mL) and piperazine -1- t-butyl formate (3.30g, 17.69mmol) is added.By the reaction It is stirred 0.5 hour at 50 DEG C.THF is filtered, then cool down and forms crystal, it is filtered out after a few hours.It is dried overnight, Solid crystal weighing 5.6g.Filtrate THF is evaporated and remaining solid is allocated between ethyl acetate and water.More Product insoluble in any and filter out.Ethyl acetate is dry, it is concentrated and is added hexane, obtains crystal, obtains 4- (6- Chloro- 3,5- dicyano -4- ethylpyridine -2- base) piperazine -1- t-butyl formate (6.4g, 17.03mmol, 96% yield).LCMS M/z=276.0 [M+H]+。
Step 2:2- ((3,5- dicyano -4- ethyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine, trifluoroacetate
Thioacetic acid S- (2- amino -2- oxo -1- phenylethyl) ester (in 62 step 5 of embodiment is described into conjunction It is dissolved in ethyl alcohol (50mL) at 2.171g, 10.38mmol), is heated to 70 DEG C and NaBH is added portionwise4(0.423g, 11.17mmol).After 30 minutes, it is bubbled and stops, then by 4- (chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-) piperazine -1- T-butyl formate (3g, 7.98mmol) is dissolved in the alcohol mixture (120mL) of warm and is slowly added to 50mL tetrahydrofuran simultaneously The reaction is heated 30 minutes at 70 DEG C.Solvent is evaporated and the thick material is dissolved in DCM and is washed with water.By DCM sulphur Sour sodium is dry simultaneously to be evaporated, and the crude product of 3.5g is obtained, and is dissolved in DCM and loading is to 80g silicagel column.When pressure closes instrument When, terminated with the elution of ethyl acetate/hexane 12-75%.The column is cut into (sawed open) and by with DCM/1% methanol It is sirred and separated zone of a crystal and filters out silica gel, obtain 4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyan Base -4- ethylpyridine -2- base) piperazine -1- t-butyl formate (1.85g, 3.65mmol, 46% yield).LCMS m/z=507.2 [M+H]+.The product of the alcohol is dissolved in 30mL DCM and 20mL TFA is added.It is stirred at room temperature 1 hour and is steamed TFA It sends out and is handled and evacuated with DCM.Lead to Crystallization with DCM grinding.Obtain 2- ((3,5- dicyano -4- ethyl -6- (piperazine - 1- yl) pyridine -2- base) sulfenyl) -2- phenyl-acetamides, trifluoroacetate (1.9g, 3.65mmol).The intermediate is not characterized as Trifluoroacetate.
Step 3:2- ((3,5- dicyano -4- ethyl -6- (4- (oxazole -2- ylmethyl) piperazine -1- base) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides
By 2- ((3,5- dicyano -4- ethyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides, three Fluoroacetate (describing synthesis, 215mg, 0.413mmol in 176 step 2 of embodiment) is dissolved in methylene chloride (15mL) and adds Enter DIEA (0.144mL, 0.826mmol), acetic acid (0.047mL, 0.826mmol) then is added, oxazole -2- formaldehyde is then added (80mg, 0.826mmol).The reaction is stirred 30 minutes and sodium triacetoxy borohydride (448mg, 2.116mmol) is added. The reaction is stirred 18 hours at 25 DEG C.The DCM solution is washed with water, dry and loading to 12 grams of silicagel columns and with acetic acid second Ester/ethyl alcohol 4-25% elution, is then eluted with the ethyl acetate solution of 25% ethyl alcohol, and the ammonium hydroxide elution of 1% total amount obtains 2- ((3,5- dicyano -4- ethyl -6- (4- (oxazole -2- ylmethyl) piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl second Amide (150mg, 0.308mmol).1H NMR (400MHz, DMSO-d6) δ ppm 1.06-1.28 (m, 3H) 2.59 (t, J= 4.69Hz, 4H) 2.68-2.85 (m, 2H) 3.76 (s, 2H) 3.89 (d, J=4.82Hz, 4H) 5.53 (s, 1H) 7.21 (s, 1H) 7.38 (s, 4H) 7.50 6 (s, 2H) 7.84-7.95 (m, 1H) 8.11 (d, J=0.76Hz, 1H).LCMS m/z=488.2 [M+ H]+。
Embodiment 177
2- ((6- (4- ((1H- pyrroles -2- base) methyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) Sulfenyl) -2- phenyl-acetamides
By 2- ((3,5- dicyano -4- ethyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides 2, 2,2- trifluoroacetates (describing synthesis, 215mg, 0.413mmol in 176 step 2 of embodiment) are dissolved in methylene chloride (15mL) and DIEA (0.144mL, 0.826mmol).Then acetic acid (0.047mL, 0.826mmol) is added, 1H- pyrrole is then added Cough up -2- formaldehyde (79mg, 0.826mmol).By the reaction stir 30 minutes and be added sodium triacetoxy borohydride (350mg, 1.652mmol).The reaction is stirred 18 hours at 25 DEG C.The DCM solution is washed with water, with sodium sulphate drying and is evaporated.It will Its loading is eluted to 12g silicagel column and with ethyl acetate/ethyl alcohol 4-25%, and then with the ethyl acetate of 25% ethyl alcohol, (it contains 1% ammonium hydroxide) solution elution.Obtain 2- ((6- (4- ((1H- pyrroles -2- base) methyl) piperazine -1- base) -3,5- dicyano - 4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides (75mg, 0.154mmol, 37% yield).LCMS m/z=486.2 [M +H]+。1H NMR (400MHz, DMSO-d6) δ ppm 1.13-1.33 (t, 3H) 2.4-2.46 (t, 2H) 2.75 (q, J=7.52Hz, 2H) 2.9-3.3 (t, 2H) 3.41-3.56 (m, 2H) 3.87 (br.s., 4H) 5.52 (s, 1H) 5.84-6.04 (m, 2H) 6 6.67 (d, J=1.52Hz, 1H) 7.21-7.44 (m, 4H) 7.45-7.57 (m, 2H) 7.88 (s, 1H) 10.71 (br.s., 1H).
Embodiment 178
2- ((3,5- dicyano -6- (- 2 (1H)-yl of 3,4- dihydro -2,7- benzodiazine) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides
By 2- ((chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-) sulfenyl) -2- phenyl-acetamides (in embodiment 52, Synthesis, 60.5mg, 0.170mmol are described in step 1) and 1,2,3,4- tetrahydro -2,7- benzodiazine hydrochlorides (40mg, It 0.234mmol) adds to bottle and is suspended in tetrahydrofuran (6mL).DIPEA (0.044mL, 0.254mmol) is added and mixes this Conjunction object is heated to 65 DEG C and continues 2 hours, then heats 3 hours at 55 DEG C.The mixture is concentrated and material is passed through into silicagel pad (EtOAc；1:1EtOAc:IPA, then 3:1EtOAc:EtOH w/1%NH4OH), (30x50 then is purified in alkaline HPLC RP Column；20-80% water w/0.1%NH4OH/ acetonitrile), be then freeze-dried, obtain 2- ((3,5- dicyano -6- (3,4- dihydro -2, 7- benzodiazine -2 (1H)-yl) -4- ethylpyridine -2- base) sulfenyl) (15mg, 0.032mmol, 19% are produced -2- phenyl-acetamides Rate).LCMS m/z=455.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.50 (s, 1H) 8.40 (d, J= 5.07Hz, 1H) 8.00 (s, 1H) 7.56 (d, J=7.10Hz, 2H) 7.31-7.50 (m, 4H) 7.29 (d, J=4.82Hz, 1H) (5.63 s, 1H) 5.00 (q, J=16.73Hz, 2H) 3.99-4.12 (m, 2H) 3.03 (t, J=5.70Hz, 2H) 2.80 (q, J= 7.60Hz, 2H) 1.23 (t, J=7.48Hz, 3H).
Embodiment 181:
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (pyrrole Pyridine -3- base) acetamide
Step 1: methanesulfonic acid 2- amino -2- oxo -1- (pyridin-3-yl) ethyl ester
In room temperature, to 2- hydroxyl -2- (pyridin-3-yl) acetamide (400mg, 2.63mmol) and Et3N (0.733mL, 5.26mmol) methane sulfonyl chloride (361mg, 3.15mmol) is added in the agitating solution in tetrahydrofuran (20mL) and by gained Mixture is stirred at room temperature 5 hours.The reaction mixture is concentrated, the residue silica gel chromatography (is then used into DCM/ MeOH, 50:1 elution), methanesulfonic acid 2- amino -2- oxo -1- (pyridin-3-yl) ethyl ester (300mg, 50% yield) is obtained, For brown solid.LCMS m/z=230.9 [M+H]+。
Step 2:2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulphur Base) -2- (pyridin-3-yl) acetamide
By the chloro- 4- ethyl -6- of (S) -2- (3- hydroxyl pyrrolidine -1- base) pyridine -3,5- dimethoxy nitrile (in embodiment 168, Synthesis, 300mg, 1.08mmol are described in step 1), thioacetic acid potassium (149mg, 1.30mmol) is in N, N- dimethyl formyl Solution in amine (15mL) is stirred at room temperature 30 minutes, and methanesulfonic acid 2- amino -2- oxo -1- (pyridine -3- then is added in room temperature Base) ethyl ester (300mg, 1.30mmol) and Et3N (0.302mL, 2.17mmol).It is small that gained mixture is stirred at room temperature 12 When.It is extracted by the reaction mixture down to water (50mL) and with EtOAc (50mL x 2).Combined organic layer is dry and dense Then residue silica gel column purification (is eluted) with DCM/MeOH, 100:1, obtains 2- ((3,5- dicyano -4- second by contracting Base -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) (120mg, 27% produces -2- (pyridin-3-yl) acetamide Rate), it is white solid.LCMS m/z=409.0 [M+H]+。1H NMR (400MHz, DMSO) δ ppm 8.85-8.65 (m, 1H), 8.62-8.42 (m, 1H), 8.15-7.98 (m, 1H), 7.95-7.80 (m, 1H), 7.60-7.25 (m, 2H), 5.70 (s, 1H), 5.30-5.05 (m, 1H), 4.50-4.30 (m, 1H), 4.10-3.60 (m, 4H), 2.85-2.65 (m, 2H), 2.10-1.82 (m, 2H), 1.30-1.10 (m, 3H).
Embodiment 182
2- ((6- (4- ((1H- pyrroles -3- base) methyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) Sulfenyl) -2- phenyl-acetamides
By 2- ((3,5- dicyano -4- ethyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides 2, 2,2- trifluoroacetates (describing synthesis, 215mg, 0.413mmol in 176 step 2 of embodiment) are dissolved in methylene chloride (15mL) and DIEA (0.144mL, 0.826mmol).Acetic acid (0.047mL, 0.826mmol) is added, 1H- pyrrole is then added Cough up -3- formaldehyde (79mg, 0.826mmol).By the reaction stir 30 minutes and be added sodium triacetoxy borohydride (350mg, 1.652mmol).The reaction is stirred 18 hours at 25 DEG C.The DCM solution is washed with water, drying is simultaneously evaporated.Extremely by its loading 12g silicagel column, column DCM containing 5mL, and eluted with ethyl acetate/ethyl alcohol 4-25%, then with the ethyl acetate of 25% ethyl alcohol Solution (containing 1% ammonium hydroxide) elution.Obtain 2- ((6- (4- ((1H- pyrroles -3- base) methyl) piperazine -1- base) -3,5- dicyan Base -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides (70mg, 0.142mmol, 35% yield) LCMS m/z=486.2 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 1.10-1.29 (m, 3H) 2.45 (br.s., 4H) 2.76 (br.s., 2H) (3.4-3.5 m, 2H) 3.86 (br.s., 4H) 5.52 (s, 1H) 5.95-6.05 (m, 1H) 6.65 (m, 2H) 7.37 (d, J= 7.86Hz, 4H) 7.45-7.60 (m, 2H) 7.91 (s, 1H) 10.59-10.73 (m, 1H).
Embodiment 183
2- ((3,5- dicyano -4- ethyl -6- (4- (isoxazole -3- ylmethyl) piperazine -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides
By 2- ((3,5- dicyano -4- ethyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides 2, 2,2- trifluoroacetates (describing synthesis, 215mg, 0.413mmol in 176 step 2 of embodiment) are dissolved in methylene chloride In (15mL) and DIEA (0.144mL, 0.826mmol).It is added acetic acid (0.047mL, 0.826mmol), isoxazole-is then added 3- formaldehyde (80mg, 0.826mmol).By the reaction stir 30 minutes and be added sodium triacetoxy borohydride (350mg, 1.652mmol).The reaction is stirred 18 hours at 25 DEG C.The DCM solution is washed with water.The DCM solution is done with sodium sulphate It is dry and evaporate.By the thick material loading to 12g silicagel column, washed containing 25mL DCM, and with ethyl acetate/ethyl alcohol 4-25% It is de-, then with the ethyl acetate solution of 25% ethyl alcohol (containing 1% ammonium hydroxide) elution.Obtain 2- ((3,5- dicyano -4- ethyl - 6- (4- (isoxazole -3- ylmethyl) piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides (130mg, 0.267mmol, 65% yield).LCMS m/z=488.2 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm2.53-2.56 (m, 4H) 2.61- 2.88 (m, 2H) 3.61-3.77 (m, 2H) 3.8-3.9 (m, 4, H) 5.51 (s, 1H), 6.60 (d, J=1.77Hz, 1H) 7.19- 7.42 (m, 5H) 7.49-7.51 (m, 1H) 7.90 (s, 1H) 8.91 (d, J=1.52Hz, 1H).
Embodiment 184
2- ((3,5- dicyano -4- ethyl -6- (4- (oxazole -5- ylmethyl) piperazine -1- base) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides
By 2- ((3,5- dicyano -4- ethyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides 2, 2,2- trifluoroacetates (describing synthesis, 215mg, 0.413mmol in 176 step 2 of embodiment) are dissolved in methylene chloride (15mL) and DIEA (0.144mL, 0.826mmol).It is added acetic acid (0.047mL, 0.826mmol), oxazole -5- first is then added Aldehyde (80mg, 0.826mmol).By the reaction stir 30 minutes and be added sodium triacetoxy borohydride (350mg, 1.652mmol).The reaction is stirred 18 hours at 25 DEG C.The DCM solution is washed with water, with sodium sulphate drying and is evaporated.It will Its loading is to 12g silicagel column, DCM containing 15mL, and with ethyl acetate/ethanol elution (4-25% ethyl alcohol), then with 25% second Ethyl acetate solution (containing 1% ammonium hydroxide) elution of alcohol.The product of purifying is further purified on Gilson reversed-phase HPLC, With gradient elution of 0.1% ammonium hydroxide in water and acetonitrile (10-90%), 2- ((3,5- dicyano -4- ethyl -6- are obtained (4- (oxazole -5- ylmethyl) piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides (45mg, 0.092mmol).LCMS M/z=488.2 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 1.20 (t, J=7.60Hz, 4H) 2.75 (d, J= 7.60Hz, 2H) 3.32 (s, 1H) 3.68 (s, 2H) 3.88 (br.s., 5H) 5.52 (s, 1H) 7.12 (s, 1H) 7.30-7.43 (m, 5H) 7.44-7.57 (m, 2H) 7.91 (s, 1H) 8.35 (s, 1H).
Embodiment 185
2- ((3,5- dicyano -4- ethyl -6- (4- (isoxazole -4- ylmethyl) piperazine -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides
By 2- ((3,5- dicyano -4- ethyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides 2, 2,2- trifluoroacetates (describing synthesis, 215mg, 0.413mmol in 176 step 2 of embodiment) are dissolved in methylene chloride (15mL) and DIEA (0.161mL, 0.826mmol).It is added acetic acid (0.047mL, 0.826mmol), isoxazole -4- is then added Formaldehyde (80mg, 0.826mmol).By the reaction stir 30 minutes and be added sodium triacetoxy borohydride (350mg, 1.652mmol).The reaction is stirred 18 hours at 25 DEG C.The DCM solution is washed with water.The DCM solution is done with sodium sulphate Dry, evaporation is eluted, then with the ethyl acetate of 25% ethyl alcohol in 12g silica gel column purification with ethyl acetate/ethyl alcohol (4-25%) (containing 1% ammonium hydroxide) elution.Obtained partially purified product is further purified with Gilson HPLC, with 0.1% hydrogen-oxygen Change ammonium in the gradient elution of water and acetonitrile (10-90%).Obtain 2- ((3,5- dicyano -4- ethyl -6- (4- (isoxazole -4- base Methyl) piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides (150mg, 0.308mmol, 75% yield) LCMS m/z =488.2 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 1.01-1.39 (m, 3H) 1.46-1.48 (m, 4H) 2.70- 2.76 (m, 2H) 3.46-3.48 (s, 2H) 3.86-3.88 (t, J=4.82Hz, 4H) 5.51 (s, 1H) 7.17-7.46 (m, 4H) 7.61 (m, 2H) 7.90 (s, 1H) 8.60 (m, 1H) 8.90 (s, 1H).
Embodiment 186:
3- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) oxetanyl -3- formamide
Step 1:4- (3- ((tertbutyloxycarbonyl) amino) oxetanyl -3- formamido group) piperidines -1- benzyl formate
By 3- ((tertbutyloxycarbonyl) amino) oxetanyl -3- formic acid (500mg, 2.302mmol), 4- amino piperazine Pyridine -1- benzyl formate (593mg, 2.53mmol), 1H- benzo [d] [1,2,3] triazole -1- alcohol (373mg, 2.76mmol) add to In N,N-dimethylformamide (25mL).The mixture is stirred 12 hours at 25 DEG C, water (30mL) then is added.By the mixing Object is extracted with ethyl acetate (30mL x 3), dry with sodium sulphate, is concentrated and with flash column chromatography, and 4- (3- ((uncle is obtained Butoxy carbonyl) amino) oxetanyl -3- formamido group) piperidines -1- benzyl formate (630mg, 63% yield).LCMS m/ Z=456.1 [M+Na]+。
Step 2:(3- (piperidin-4-yl carbamoyl) oxetanyl -3- base) t-butyl carbamate
By 4- (3- ((tertbutyloxycarbonyl) amino) oxetanyl -3- formamido group) piperidines -1- benzyl formate (750mg, 1.730mmol) and Pd/C (10%, 75mg) are added in methanol (25mL).By the mixture at 25 DEG C in hydrogen filling It is stirred 2 hours under balloon.The mixture is filtered, is concentrated and with flash column chromatography, (3- (piperidin-4-yl amino first is obtained Acyl group) oxetanyl -3- base) t-butyl carbamate (460mg, 89% yield).LCMS m/z=299.8 [M+H]+。
Step 3:(3- ((1- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) piperidin-4-yl) carbamoyl) Oxetanyl -3- base) t-butyl carbamate
By (3- (piperidin-4-yl carbamoyl) oxetanyl -3- base) t-butyl carbamate (460mg, 1.537mmol), chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in 3 step 2 of embodiment, 347mg, 1.537mmol) added in methylene chloride (30mL) with triethylamine (311mg, 3.07mmol).The mixture is stirred 6 at 25 DEG C Hour, then washed with water (30mL).Organic layer is dried and concentrated with sodium sulphate.The residue flash column chromatography is pure Change, obtains (3- ((1- (chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-) piperidin-4-yl) carbamoyl) oxa- ring fourth Alkyl -3- base) t-butyl carbamate (540mg, 72% yield).LCMS m/z=511.1 [M+Na]+。
Step 4:(3- ((1- (3,5- dicyano -4- ethyl -6- mercaptopyridine -2- base) piperidin-4-yl) carbamyl Base) oxetanyl -3- base) t-butyl carbamate
By (3- ((1- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) piperidin-4-yl) carbamoyl) oxa- Cyclobutane base -3- base) t-butyl carbamate (220mg, 0.450mmol) and thioacetic acid potassium (61.7mg, 0.540mmol) plus To N,N-dimethylformamide (12mL).The mixture is stirred 4 hours at 20 DEG C, is washed with water (20mL) and uses ethyl acetate (20mL x 3) extraction.Organic layer is concentrated, (3- ((1- (3,5- dicyano -4- ethyl -6- mercaptopyridine -2- base) piperazine is obtained Pyridine -4- base) carbamoyl) oxetanyl -3- base) t-butyl carbamate (150mg, 69% yield).LCMS m/z =509.1 [M+Na]+。
Step 5:(3- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) carbamoyl) oxetanyl -3- base) t-butyl carbamate
By (3- ((1- (3,5- dicyano -4- ethyl -6- mercaptopyridine -2- base) piperidin-4-yl) carbamoyl) oxygen Azetidinyl -3- base) t-butyl carbamate (150mg, 0.308mmol), methanesulfonic acid 2- amino -2- oxo -1- phenyl second Base ester (describing synthesis, 106mg, 0.462mmol in 3 step 5 of embodiment) and potassium carbonate (85mg, 0.617mmol) add to In N,N-dimethylformamide (15mL).The mixture is stirred 12 hours at 40 DEG C, water (30mL) then is added.By the mixing Object is extracted with ethyl acetate (20mL x 3).Organic layer is dry with sodium sulphate, is concentrated and with flash column chromatography, obtains (3- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl) Carbamoyl) oxetanyl -3- base) t-butyl carbamate (180mg, 94% yield).LCMS m/z=620 [M+ H]+。
Step 6:3- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- Ethylpyridine -2- base) piperidin-4-yl) oxetanyl -3- formamide
(3- ((1- is added in the solution in methylene chloride (12mL) to 2,2,2- trifluoroacetic acids (2mL, 0.387mmol) (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl) amino Formoxyl) oxetanyl -3- base) t-butyl carbamate (240mg, 0.387mmol).The mixture is stirred at 25 DEG C 3 hours, water (20mL) then is added.The mixture is extracted with DCM (20mL x 3).The organic phase is dry with sodium sulphate, It is concentrated and preparative-HPLC is used to purify, obtain 3- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) - 3,5- dicyano -4- ethylpyridine -2- bases) piperidin-4-yl) oxetanyl -3- formamide (78mg, 39% yield). LCMS m/z=520.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.01 (dd, J=45.0,37.2Hz, 2H), 7.52 (d, J=7.1Hz, 2H), 7.45-7.22 (m, 3H), 5.53 (s, 1H), 5.17 (br.s, 1H), 4.77 (d, J=6.2Hz, 2H), 4.51 (t, J=14.1Hz, 2H), 4.38 (d, J=6.3Hz, 2H), 4.09-3.85 (m, 1H), 3.46-3.19 (m, 2H), 2.89-2.65 (m, 2H), 1.89 (d, J=12.6Hz, 2H), 1.65-1.42 (m, 2H), 1.21 (t, J=7.6Hz, 3H).
Embodiment 187
2- ((6- (4- ((1H- pyrazoles -4- base) methyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) Sulfenyl) -2- phenyl-acetamides
By 2- ((3,5- dicyano -4- ethyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides 2, 2,2- trifluoroacetates (describing synthesis, 215mg, 0.413mmol in 176 step 2 of embodiment) are dissolved in methylene chloride (15mL) and DIEA (0.144mL, 0.826mmol).It is added acetic acid (0.047mL, 0.826mmol), 1H- pyrazoles-is then added 4- formaldehyde (79mg, 0.826mmol), by the reaction stir 30 minutes and be added sodium triacetoxy borohydride (350mg, 1.652mmol).The reaction is stirred 18 hours at 25 DEG C.By the DCM solution water, then saturated sodium bicarbonate aqueous solution is used Water washing.The DCM solution is dry, it then evaporates and grinds obtained solid with ethyl acetate, the product of alcohol is obtained after filtering. The solid is dried overnight in vacuum drying oven, obtains 2- ((6- (4- ((1H- pyrazoles -4- base) methyl) piperazine -1- base) -3,5- Dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides (75mg, 0.149mmol, 36% yield) LCMS m/z= 487.2[M+H]+。1H NMR (400MHz, DMSO-d6) 2.44 (br.s., 4H) 2.75 of δ ppm 1.20 (t, J=7.60Hz, 3H) (d, J=7.60Hz, 2H) 3.44 (s, 2H) 3.86 (d, J=4.82Hz, 4H) 5.52 (s, 1H) 7.28-7.44 (m, 4H) 7.46- 7.61 (m, 5H) 7.91 (s, 1H).
Embodiment 188
2- ((6- (4- ((1H- imidazoles -5- base) methyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) Sulfenyl) -2- phenyl-acetamides
By 2- ((3,5- dicyano -4- ethyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides 2, 2,2- trifluoroacetates (describing synthesis, 215mg, 0.413mmol in 176 step 2 of embodiment) are dissolved in methylene chloride (15mL) and DIEA (0.144mL, 0.826mmol).It is added acetic acid (0.047mL, 0.826mmol), 1H- imidazoles-is then added 5- formaldehyde (79mg, 0.826mmol).By the reaction stir 30 minutes and be added sodium triacetoxy borohydride (438mg, 2.065mmol).The reaction is stirred 18 hours at 25 DEG C.DCM (15mL) is added in the reaction and the solution unsaturated carbonate Hydrogen sodium water solution and water washing.It is the DCM sodium sulphate of the separation is dry and evaporate, obtain crude product, by its It is purified on Gilson reversed-phase HPLC, elutes (10-90% gradient) with the water and acetonitrile solution of 0.1% ammonium hydroxide.Obtain 2- ((6- (4- ((1H- imidazoles -5- base) methyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl Acetamide (45mg, 0.092mmol, 22% yield) LCMS m/z=487.1 [M+H]+。1H NMR (400MHz, DMSO-d6)δ Ppm 1.03-1.37 (m, 3H) 2.5-2.6 (m, 2H) 2.73-2.74 (m, 2H) 3.31-3.33 (m, 2H) 3.50-3.56 (m, 2H) 3.86 (4H, m) 3.8 (2H, m) 5.52 (s, 1H) 6.99-7.19 (m, 1H) 7.25-7.41 (m, 3H) 7.48-7.49 (m, 1H) 7.56-7.57 (m, 1H) 7.91 (s, 1H) 11.91 (s, 1H).
Embodiment 189:
2- ((3,5- dicyano -4- ethyl -6- (4- (1- hydroxy-2-methyl propyl- 2- yl) piperazine -1- base) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides
Step 1:2- (4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperazine -1- base) -2 Methylpropionic acid
To 2- ((3,5- dicyano -4- ethyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides, three Fluoroacetate (describing synthesis, 1040mg, 2.00mmol in 176 step 2 of embodiment) and K2CO3(552mg, 4.00mmol) Solution in acetonitrile (20mL) is added at one time 2 bromo 2 methyl propionic acid (667mg, 4.00mmol) in second under nitrogen at room temperature Solution in nitrile (20mL) continues 1 minute.The reaction mixture is stirred 15 hours at 25 DEG C, then uses ethyl acetate (50mL) is diluted and is washed with water (50mL).Water layer is acidified with 3N HCl solution and ethyl acetate (50mL) is used to extract.To have Machine layer is washed with saturated brine (25mL) and water (50mL), with sodium sulphate drying and is evaporated in vacuo, is obtained raw product (600mg, 61% yield), is yellow solid.LCMS m/z=493 [M+H]+。
Step 2:2- ((3,5- dicyano -4- ethyl -6- (4- (1- hydroxy-2-methyl propyl- 2- yl) piperazine -1- base) pyrrole Pyridine -2- base) sulfenyl) -2- phenyl-acetamides
To 2- (4- (6- ((2- amino -2- oxo -1- phenylethyl) the sulfenyl) -3,5- two stirred under nitrogen at room temperature Cyano -4- ethylpyridine -2- base) piperazine -1- base) -2 Methylpropionic acid (400mg, 0.812mmol) is in tetrahydrofuran (10mL) Solution in be added at one time solution of 1, the 1 '-carbonyl dimidazoles (263mg, 1.62mmol) in tetrahydrofuran (10mL), hold It is 1 minute continuous.The reaction mixture is stirred 5 hours at 25 DEG C.Then the reaction mixture is added dropwise to NaBH at 0 DEG C4 The solution of (61.4mg) in water (5mL).Then the reaction is stirred 5 hours under a nitrogen.By the reaction ethyl acetate (50mL) extraction, is washed with 2M hydrochloric acid (10mL), water (50mL) and saturated brine (50mL), is dried and concentrated with sodium sulphate.It will The thick material is purified with preparative-HPLC, obtains 2- ((3,5- dicyano -4- ethyl -6- (4- (1- hydroxy-2-methyl propyl- 2- Base) piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides (11mg, 3% yield) are white solid.LCMS m/z =479.1 [M+H]+。1H NMR (400MHz, MeOD) δ ppm 7.56 (d, J=6.4Hz, 2H), 7.47-7.35 (m, 3H), 5.51 (s, 1H), 4.11 (s, 4H), 3.58 (s, 2H), 3.06 (s, 4H), 2.93 (q, J=7.6Hz, 2H), 1.32 (t, J=7.6Hz, 3H), 1.22 (s, 6H).
Embodiment 190
2- ((6- (4- ((1H- imidazoles -2- base) methyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) Sulfenyl) -2- phenyl-acetamides
By 2- ((3,5- dicyano -4- ethyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides, 2, 2,2- trifluoro-acetates (describing synthesis, 215mg, 0.413mmol in 176 step 2 of embodiment) are dissolved in methylene chloride (25mL) and n,N-diisopropylethylamine (0.144mL, 0.826mmol) is added.Into the solution be added acetic acid (0.061mL, 1.058mmol), 1H- imidazoles -2- formaldehyde (79mg, 0.826mmol) then is added.By the mixture stir 3 hours, then plus Enter sodium triacetoxy borohydride (438mg, 2.065mmol).The reaction is stirred 18 hours at 25 DEG C.The solution is saturated Sodium bicarbonate aqueous solution washing, is then stirred 2 hours with 1N sodium hydroxide.It separates each layer and dries organic phase sodium sulphate. The solvent is evaporated and grinds resulting white solid with ethyl acetate.The solid is collected, is washed with ethyl acetate, then It is washed with hexane and dry in 40 DEG C of vacuum ovens, obtains 2- ((6- (4- ((1H- imidazoles -2- base) methyl) piperazine -1- Base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides (105mg, 51% yield).LCMS m/z= 487.1[M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 1.20 (t, J=7.60Hz, 3H), 2.52-2.55 (m, 4H), 2.75 (d, J=7.60Hz, 2H), 3.58 (d, J=1.01Hz, 2H), 3.88 (d, J=3.04Hz, 4H), 5.52 (s, 1H), 6.83 (s, 1H), 7.07 (s, 1H), 7.30-7.42 (m, 4H), 7.46-7.54 (m, 2H), 7.91 (s, 1H), 11.90-11.99 (m, 1H).
Embodiment 191
2- ((3,5- dicyano -6- (dimethylamino) -4-methoxypyridine -2- base) sulfenyl) -2- phenyl-acetamides
2- ((6- amino -3,5- dicyano -4-methoxypyridine -2- base) sulfenyl) -2- phenyl-acetamides (are being implemented Example 142 describes synthesis, 100mg, 0.206mmol in step 3) and copper chloride (II) (70mg, 0.521mmol) add to bottle In and be suspended in acetonitrile (10mL).The mixture is heated to 50 DEG C and continues 5 minutes.By nitrite tert-butyl (0.06mL, It 0.506mmol) is added slowly to the mixture and stirs material 60 minutes at 50 DEG C.After 1 hour, by the tertiary fourth of 0.03mL nitrous acid Ester and 40mg CuCl2Add to the mixture of the heating.By small silicagel pad/It filters and uses EtOAc/EtOH (4:1) Washing, the filtrate handle (80mg, 0.981mmol) with dimethylamine hydrochloride and 3mL DIPEA are added to the mixture.Solution becomes It is blue.Concentrate solution；By residue in C18 reverse phase isco purifying (0-50-100%0.1%NH4OH aqueous solution/acetonitrile) and by institute It needs fraction to merge and EtOAc (3x) and salt water is used to extract.By combined organic matter MgSO4It is dried, filtered and concentrated, obtains 2- ((3,5- dicyano -6- (dimethylamino) -4-methoxypyridine -2- base) sulfenyl) -2- phenyl-acetamides (28mg, 0.076mmol, 37% yield).LCMS m/z=368.3 [M+H]+。1H NMR (400MHz, DMSO-d6)δppm 7.85-7.99 (m, 1H) 7.46-7.59 (m, 2H) 7.24-7.46 (m, 4H) 5.58 (s, 1H) 4.23 (s, 3H) 3.31 (s, 6H).
Embodiment 192:
2- ((3,5- dicyano -6- (dimethylamino) -4- ethoxy pyridine -2- base) sulfenyl) -2- phenyl-acetamides
The chloro- 4- ethoxy pyridine -3,5- dimethoxy nitrile of step 1:2- amino -6-
Under a nitrogen, second is added into the mixture of tetracyanoethylene (3g, 23mmol) and urea (478mg, 7.96mmol) Alcohol (10mL).The darkviolet mixture is heated to 35 DEG C and continues 15 minutes, is cooled to room temperature and uses Et2O (40mL) dilution.It will The mixture, which is cooled to -78 DEG C, to be continued 3 hours and by solid with cold Et2O is washed and is air-dried, and obtains the white powder of 2.59g. Under a nitrogen, by the powder (2.59g) as solution (5mL) in ethanol add to malononitrile (0.99mL, 15.59mmol) and Potassium tert-butoxide (1.75g, 15.59mmol) is in 60 DEG C of mixtures in ethyl alcohol (5mL).The mixture is heated to reflux 2 hours, Cooling simultaneously removes the solvent under reduced pressure.By obtained solid Et2O grinding is simultaneously dried in vacuo at 50 DEG C, obtains the light brown of 3.5g Powder.Concentrated hydrochloric acid (6mL, 194mmol) is added dropwise in the mixture in acetone (25mL) to the powder (1.5g).Gained is mixed Object heats 17 hours at 50 DEG C, then cools down, and pours into water (50mL) and stirs 15 minutes.By the solid with water (2x 25mL) It washs and is dried in vacuo at 50 DEG C, obtain chloro- 4- ethoxy pyridine -3, the 5- dimethoxy nitrile of 2- amino -6- (672mg, 45% yield), It is brown ceramic powder.LCMS m/z=221.0 [M-H]-。
Step 2:2- ((6- amino -3,5- dicyano -4- ethoxy pyridine -2- base) sulfenyl) -2- phenyl-acetamides
At 75 DEG C, (retouched in 62 step 5 of embodiment to thioacetic acid S- (2- amino -2- oxo -1- phenyl-ethyl group) ester State synthesis, 493mg, 2.36mmol) sodium borohydride (127mg, 3.37mmol) is added in the solution in ethyl alcohol (15mL).It will The mixture stir 15 minutes and by acquired solution add to chloro- 4- ethyoxyl-pyridine -3, the 5- dimethoxy nitrile of 2- amino -6- (500mg, 2.25mmol) heated 15 minutes in the suspension of the heat in ethyl alcohol (10mL) and at 75 DEG C.The mixture is cooled to room temperature, Then cooling in ice-cold water-bath.Gained mixture is filtered, with water (2x 10mL), Et2O (2x 10mL) is washed and at 50 DEG C Vacuum drying, obtains 2- [(6- amino -3,5- dicyano -4- ethyoxyl -2- pyridyl group) sulfanyl] -2- phenvl-acetamide (491mg, 62% yield), is white powder, is used for subsequent step and does not have to be further purified.LCMS m/z= 352.2[M-H]-。
Step 3:2- ((the bromo- 3,5- dicyano -4- ethoxy pyridine -2- base of 6-) sulfenyl) -2- phenyl-acetamides
Under a nitrogen, to 2- [(6- amino -3,5- dicyano -4- ethyoxyl -2- pyridyl group) sulfanyl] -2- phenyl-second Amide (460mg, 1.30mmol) be added in the suspension in acetonitrile (40mL) nitrite tert-butyl (0.27mL, 2.28mmol), copper bromide (II) (494mg, 2.21mmol) is then added and the mixture is heated to 75 DEG C and continues 30 minutes. The mixture is cooling, it is adsorbed in SiO2(2.5g) and in SiO2Upper progress chromatogram purification (12g RediSep column), uses 0- 25%EtOAc:DCM obtains 2- [(bromo- 3, the 5- dicyano -4- ethyoxyl -2- pyridyl group of 6-) sulfanyl] -2- phenvl-acetamide (47% yield of 254mg), is yellow powder.LCMS m/z=417.1 [M-H]-。
Step 4:2- ((3,5- dicyano -6- (dimethylamino) -4- ethoxy pyridine -2- base) sulfenyl) -2- phenyl second Amide
To 2- [(bromo- 3, the 5- dicyano -4- ethyoxyl -2- pyridyl group of 6-) sulfanyl] -2- phenvl-acetamide (40mg, Dimethylamine (0.24mL, 0.48mmol) 0.10mmol) is added in the solution in THF (2mL) and stirs the mixture in room temperature It mixes 1 hour.The mixture is diluted with water (10mL), is stirred 15 minutes, filtering, with water (2x 10mL), Et2O (10mL) washing And be dried in vacuo at 50 DEG C, obtain 2- [[3,5- dicyano -6- (dimethylamino) -4- ethyoxyl -2- pyridyl group] sulfanyl] - 2- phenvl-acetamide (30mg, 82% yield), is pale powder.LCMS m/z=380.2 [M-H]-。1H NMR (300MHz, DMSO-d6) δ ppm 7.91 (s, 1H), 7.54-7.48 (m, 2H), 7.42-7.30 (m, 4H), 5.58 (s, 1H), 4.53 (q, J=7.0Hz, 2H), 3.31 (s, 6H), 1.36 (t, J=7.0Hz, 3H).
Embodiment 193
2- ((3,5- dicyano -4- ethyoxyl -6- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base) pyrrole Pyridine -2- base) sulfenyl) -2- phenyl-acetamides
Step 1:2- ((the chloro- 3,5- dicyano -4- ethoxy pyridine -2- base of 6-) sulfenyl) -2- phenyl-acetamides
2- ((6- amino -3,5- dicyano -4- ethoxy pyridine -2- base) sulfenyl) -2- phenyl-acetamides (are being implemented Example 192 describes synthesis, 355mg, 1.005mmol in step 2) be dissolved in acetonitrile (45mL) and be added copper chloride (II) (250mg, 1.859mmol).By the mixture be stirred and heated to 50 DEG C continue 5 minutes and be added dropwise nitrite tert-butyl (0.22mL, 1.856mmol).The mixture is heated to 50 DEG C and continues 1.5 hours.It is cooled to room temperature and filters out a small amount of residue.It will The filtrate is post-processed with EtOAc (3x) and salt water.By the organic matter MgSO of the merging4It dries, filters and is concentrated, on silica gel (80g column, 100%DCM- > 5%IPA is in DCM w/1%NH for purifying4In OH).Required fraction is merged and is concentrated, 2- is obtained (206mg, 0.553mmol, 55% are produced ((chloro- 3, the 5- dicyano -4- ethoxy pyridine -2- base of 6-) sulfenyl) -2- phenyl-acetamides Rate).LCMS m/z=373.1 [M+H]+。
Step 2:2- ((3,5- dicyano -4- ethyoxyl -6- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- Base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides
By 2- ((chloro- 3, the 5- dicyano -4- ethoxy pyridine -2- base of 6-) sulfenyl) -2- phenyl-acetamides (102mg, 0.274mmol) be dissolved in tetrahydrofuran (10mL) and be added 2- (Isosorbide-5-Nitrae-Diazesuberane -1- base) ethyl alcohol (59mg, 0.409mmol).The mixture is stirred at room temperature 3 hours.By the material be concentrated and on silica gel purify (40g column, 100% DCM- > 7%IPA is in DCM w/1%NH4In OH).Required fraction is merged and is concentrated, 2- ((3,5- dicyano -4- ethoxies are obtained Base -6- (4- (2- hydroxyethyl)-Isosorbide-5-Nitrae-Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides (76mg, 0.158mmol, 58% yield).LCMS m/z=481.4 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.92 (s, 1H) 4.40 (t, J=of 7.45-7.53 (m, 2H) 7.29-7.44 (m, 4H) 5.50 (s, 1H) 4.54 (q, J=6.93Hz, 2H) 5.20Hz, 1H) 3.78-3.95 (m, 4H) 3.47 (q, J=6.08Hz, 2H) 2.70-2.91 (m, 2H) 2.52-2.69 (m, 4H) 1.88 (br.s., 2H) 1.36 (t, J=6.97Hz, 3H).
Embodiment 194
2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxy-2-methyl propyl) -1,4- Diazesuberane -1- Base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides
The chloro- 4- ethyl -6- of step 1:2- (4- (2- hydroxy-2-methyl propyl) -1,4- Diazesuberane -1- base) pyrrole Pyridine -3,5- dimethoxy nitrile
At 0 DEG C, to chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (in 3 step 2 of embodiment describe synthesis, 1g, 4.42mmol) addition triethylamine (1.233mL, 8.85mmol) in agitating solution in methylene chloride (10mL), after 2 minutes, In 0 DEG C of addition 1- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -2- methyl propan-2-ol (0.838g, 4.87mmol).The reaction is existed Then mutually synthermal stirring 10 minutes is diluted with water (20mL) and is extracted with DCM (2x 10mL).By combined organic layer nothing Aqueous sodium persulfate dries, filters, and is concentrated under vacuum to dry, obtains the crude product.By the material of the crude material and independent batch (90%) and with column chromatography 150mg, LCMS purity are about purified, silica gel (100-200 mesh, with 30-40% petroleum is used for material merging Ether/ethyl acetate elution).The fraction of collection is concentrated under reduced pressure, 2- chloro- 4- ethyl -6- (4- (2- hydroxy-2-methyl third is obtained Base)-Isosorbide-5-Nitrae-Diazesuberane -1- base) pyridine -3,5- dimethoxy nitrile (1.5g) is pale solid.LCMS m/z= 362.1[M+H]+。
Step 2:2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxy-2-methyl propyl) -1,4- diaza cycloheptyl Alkane -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides
In room temperature, to the chloro- 4- ethyl -6- of 2- (4- (2- hydroxy-2-methyl propyl)-Isosorbide-5-Nitrae-Diazesuberane -1- base) Sulphur is added in the agitating solution in n,N-Dimethylformamide (10mL) in pyridine -3,5- dimethoxy nitrile (500mg, 1.382mmol) For potassium acetate (316mg, 2.76mmol) and by the solution in mutually synthermal stirring 2 hours.In room temperature, into the reaction mixture Potassium carbonate (382mg, 2.76mmol) and methanesulfonic acid 2- amino -2- oxo -1- phenylethylester is added (in 3 step 5 of embodiment Describe synthesis, 317mg, 1.382mmol) and gained mixture is stirred at room temperature 12 hours.By the reaction mixture ice Water (50mL) dilution is simultaneously extracted with ethyl acetate (2x 50mL).By combined organic layer dried, filtered with anhydrous sodium sulfate and Reduced under vacuum obtains the crude product to doing.The crude material is purified with column chromatography, using silica gel, (100-200 mesh, uses 70- The petroleum ether solution of 80% ethyl acetate elutes).The pure fraction is concentrated under reduced pressure, 2- ((3,5- dicyano -4- ethyls-are obtained 6- (4- (2- hydroxy-2-methyl propyl) -1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides (300mg, 44% yield) is brown solid.LCMS m/z=493.3 [M+H]+。1H NMR (400MHz, DMSO-d6)δppm 7.88 (s, 1H), 7.57-7.46 (m, 2H), 7.41-7.19 (m, 4H), 5.51 (s, 1H), 4.03-3.98 (m, 1H), 3.95- 3.57 (m, 4H), 3.00-2.84 (m, 2H), 2.82-2.59 (m, 4H), 2.41-2.27 (m, 2H), 1.87 (br s, 2H), 1.29-1.13 (m, 3H), 1.08-0.62 (m, 6H).
Embodiment 195
2- ((3,5- dicyano -4- ethyl -6- (4- (thiazole -5- ylmethyl) piperazine -1- base) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides
By 2- ((3,5- dicyano -4- ethyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides, 2, 2,2- trifluoro-acetates (describing synthesis, 215mg, 0.413mmol in 176 step 2 of embodiment) are dissolved in methylene chloride (15mL) and n,N-diisopropylethylamine (0.144mL, 0.826mmol) is added.Into the solution be added acetic acid (0.047mL, 0.826mmol), thiazole -5- formaldehyde (93mg, 0.826mmol) then is added.The reaction is stirred 30 minutes and triacetyl is added Oxygroup sodium borohydride (350mg, 1.652mmol).The reaction is stirred 18 hours at 25 DEG C, methylene chloride is then added (30mL).Then by the solution saturated sodium bicarbonate aqueous solution and water washing.Then by the organic phase with sodium sulphate it is dry and Concentration.The residue is ground with ethyl acetate and obtained solid is collected by filtration and is dried overnight in vacuum drying oven, Obtain 2- ((3,5- dicyano -4- ethyl -6- (4- (thiazole -5- ylmethyl) piperazine -1- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide (100mg, 46% yield).LCMS m/z=504.4 [M+H]+。1H NMR (400MHz, DMSO-d6)δppm 1.10-1.25 (m, 3H), 2.55-2.56 (4protons likely is covered by DMSO), 2.74-2.77 (m, 2H), 3.84- 3.90 (m, 6H), 5.52 (s, 1H), 7.31-7.38 (m, 4H), 7.49-7.51 (m, 2H), 7.81-7.83 (m, 1H), 7.89 (d, J=1.77Hz, 1H), 9.08 (d, J=1.77Hz, 1H).
Embodiment 196
2- ((3,5- dicyano -4- ethyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- (4- fluorophenyl) acetyl Amine, trifluoroacetate
Step 1:4- (3,5- dicyano -4- ethyl -6- mercaptopyridine -2- base) piperazine -1- t-butyl formate
To 4- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) piperazine -1- t-butyl formate (in 176 step of embodiment Synthesis, 500mg, 1.330mmol are described in rapid 1) thio second is added in the solution in n,N-Dimethylformamide (50mL) Sour potassium (304mg, 2.66mmol).The mixture is stirred overnight at 25 DEG C.By the residue loading to silicagel column, oneself is used Alkane/EtOAc elution, obtains 4- (3,5- dicyano -4- ethyl -6- mercaptopyridine -2- base) piperazine -1- t-butyl formate (400mg, 81% yield).LCMS m/z=396 [M+Na]+。
Step 2:4- (3,5- dicyano -4- ethyl -6- (1- (4- fluorophenyl) -2- methoxyl group -2- oxoethyl) pyridine - 2- yl) piperazine -1- t-butyl formate
To 4- (3,5- dicyano -4- ethyl -6- mercaptopyridine -2- base) piperazine -1- t-butyl formate (400mg, 1.071mmol) in the solution in methylene chloride (150mL) be added the bromo- 2- of 2- (4- fluorophenyl) methyl acetate (265mg, 1.071mmol) and triethylamine (108mg, 1.071mmol).The reaction mixture is stirred overnight at 25 DEG C.The reaction is dense It is eluted with hexane/EtOAc then by the residue loading to silicagel column, obtains 4- (3,5- dicyano -4- ethyls-by contracting 6- (1- (4- fluorophenyl) -2- methoxyl group -2- oxoethyl) pyridine -2- base) (400mg, 74% produces piperazine -1- t-butyl formate Rate).LCMS m/z=407 [M-Boc+H]+。
Step 3:2- ((3,5- dicyano -4- ethyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- (4- fluorobenzene Base) acetamide, trifluoroacetate
To 4- (3,5- dicyano -4- ethyl -6- ((1- (4- fluorophenyl) -2- methoxyl group -2- oxoethyl) sulfenyl) pyrrole Pyridine -2- base) piperazine -1- t-butyl formate (400mg, 0.741mmol) is bubbled ammonium hydroxide in the solution in methanol (50mL) (505mg, 29.7mmol).The mixture is stirred overnight at 25 DEG C, is then evaporated.The residual materials are dissolved in DCM (50mL) and 2, the mixture of 2,2- trifluoroacetic acids (845mg, 7.41mmol).The mixture is stirred overnight at 25 DEG C, then Evaporation.Residue preparative-HPLC is purified, 2- ((3,5- dicyano -4- ethyl -6- (piperazine -1- base) pyridines-are obtained 2- yl) sulfenyl) -2- (4- fluorophenyl) acetamide, trifluoroacetate (90mg, 23% yield).LCMS m/z=425 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 9.12 (s, 2H), 7.95 (s, 1H), 7.63-7.39 (m, 3H), 7.36-7.20 (m, 2H), 5.78 (s, 1H), 4.17-4.01 (m, 4H), 3.25 (s, 4H), 2.81 (q, J=7.5Hz, 2H), 1.23 (t, J= 7.6Hz, 3H).
Embodiment 197
2- ((3,5- dicyano -4- ethyl -6- (4- (isothiazole -4- ylmethyl) piperazine -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides
By 2- ((3,5- dicyano -4- ethyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides, 2, 2,2- trifluoro-acetates (describing synthesis, 215mg, 0.413mmol in 176 step 2 of embodiment) are dissolved in methylene chloride (15mL) and n,N-diisopropylethylamine (0.144mL, 0.826mmol) is added.Into the solution be added acetic acid (0.047mL, 0.826mmol), isothiazole -4- formaldehyde (93mg, 0.826mmol) then is added.The reaction is stirred 30 minutes and three second are added Triacetoxyborohydride (350mg, 1.652mmol).The reaction is stirred 18 hours at 25 DEG C, methylene chloride is then added (30mL).The solution is washed with water and saturated sodium bicarbonate aqueous solution.In this process, observed white solid formed and The solid by filtration is collected.The solution is dried, filtered and is concentrated by sodium sulphate, impure product is obtained.It is previously separated White solid be determined as pure 2- ((3,5- dicyano -4- ethyl -6- (4- (isothiazole -4- ylmethyl) piperazine -1- base) pyrrole Pyridine -2- base) sulfenyl) -2- phenyl-acetamides (130mg, 62% yield).LCMS m/z=504.2 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.91 (s, 1H), 8.51-8.56 (m, 1H), 7.89 (s, 1H), 7.47-7.55 (m, 2H), 7.26-7.42 (m, 4H), 5.51 (s, 1H), 3.89 (t, J=4.82Hz, 4H), 3.69 (s, 2H), 2.75 (q, J=7.60Hz, 2H), 1.20 (t, J=7.60Hz, 3H).
Embodiment 198
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (4- fluorophenyl) acetyl Amine
Step 1:2- (dimethylamino) -4- ethyl -6- mercaptopyridine -3,5- dimethoxy nitrile
(in 3 step 3 of embodiment conjunction is described to 2- chloro- 6- (dimethylamino) -4- ethylpyridine -3,5- dimethoxy nitrile Thioacetic acid potassium (700mg, 6.13mmol) is added in the solution in DMF (50mL) at 700mg, 2.98mmol).This is mixed Object is closed to be stirred overnight at 25 DEG C and use without further purification.LCMS m/z=233 [M+H]+。
Step 2:2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (4- fluorobenzene Base) methyl acetate
To 2- (dimethylamino) -4- ethyl -6- mercaptopyridine -3,5- dimethoxy nitrile (692mg, 2.98mmol) in N, N- The bromo- 2- of 2- (4- fluorophenyl) methyl acetate (736mg, 2.98mmol) and three is added in solution in dimethylformamide (50mL) Ethamine (302mg, 2.98mmol).The reaction is stirred overnight at 25 DEG C.The mixture part is evaporated and adds the residue Into ice water.Obtained solid is collected by filtration, 2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridines-are obtained 2- yl) sulfenyl) -2- (4- fluorophenyl) methyl acetate (400mg, 34% yield) is white solid.LCMS m/z=399 [M+ H]+。
Step 3:2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (4- fluorobenzene Base) acetamide
To 2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (4- fluorophenyl) second Sour methyl esters (400mg, 1.004mmol) is bubbled ammonium hydroxide (17.1mg, 1.004mmol) in the solution in methanol (50mL).It should Reaction mixture is stirred overnight at 25 DEG C.The mixture is evaporated and purifies residue preparative-HPLC, obtains 2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (4- fluorophenyl) acetamide (300mg, 78% yield).LCMS m/z=384 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.91 (s, 1H), 7.53 (td, J =7.7,1.5Hz, 1H), 7.45 (d, J=4.2Hz, 1H), 7.41 (dd, J=10.4,4.8Hz, 1H), 7.25 (dd, J= 17.2,9.7Hz, 2H), 5.84 (s, 1H), 3.33 (s, 6H), 2.77 (q, J=7.5Hz, 2H), 1.21 (t, J=7.6Hz, 3H).
Embodiment 199
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (5- fluorine pyridine -2- Base) acetamide
Step 1:2- (5- fluorine pyridine -2- base) -2- hydroxyl acetamide
At -20 DEG C, to 2- (5- fluorine pyridine -2- base) -2- ethyl (2.7g, 13.69mmol) in ethyl alcohol NaBH is added in solution in (30mL)4(0.570g, 15.06mmol).The reaction mixture is stirred 1 hour at -20 DEG C.It will The reaction is by being added saturation NH4Cl is quenched and is extracted with DCM.The organic phase is concentrated and is used flash column chromatography, uses stone Oily ether/EtOAc with the gradient elution of 0%-100%, obtain 2- (5- fluorine pyridine -2- base) -2- hydroxyl ethyl acetate (1.7g, 62% yield), it is yellow oil.In room temperature, to 2- (5- fluorine pyridine -2- base) -2- hydroxyl ethyl acetate (1.7g, 8.54mmol) NH is added in the solution in methanol (5mL)3(methanol solution of 7N, 8mL).The reaction mixture is stirred at room temperature overnight, Concentration is eluted with DCM/ methanol 0%-10% then by the residue flash column chromatography, obtains 2- (5- fluorine pyridine -2- Base) -2- hydroxyl acetamide (1g, 69% yield) is white solid.LCMS m/z=171.0 [M+H]+。
Step 2:2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (5- fluorine pyrrole Pyridine -2- base) acetamide
At 0 DEG C, to 2- (5- fluorine pyridine -2- base) -2- hydroxyl acetamide (1g, 5.88mmol) and triethylamine (1.065mL, Methane sulfonyl chloride (0.741g, 6.47mmol) 7.64mmol) is added dropwise in the solution in methylene chloride (15mL).The reaction is mixed Object is closed to be stirred at room temperature 1 hour.The reaction is washed with water and is concentrated.By the residue flash column, with DCM/ methanol It elutes (0-10%), obtains methanesulfonic acid 2- amino -1- (5- fluorine pyridine -2- base) -2- oxoethyl ester (600mg, 41% yield), It is white solid.To 2- chloro- 6- (dimethylamino) -4- ethylpyridine -3,5- dimethoxy nitrile (156mg, 0.665mmol) in N, Thioacetic acid potassium (83mg, 0.725mmol) is added in solution in dinethylformamide (10mL).The reaction mixture is existed It is stirred at room temperature 1 hour, K is then added2CO3(100mg, 0.725mmol) and methanesulfonic acid 2- amino -1- (5- fluorine pyridine -2- base) - 2- oxoethyl ester (150mg, 0.604mmol).The reaction mixture is stirred at room temperature overnight.Water (50mL) is added and by institute Mixture filtering is obtained, the crude product is obtained, it is used into flash column chromatography, (0-10%) is eluted with DCM/ methanol, obtains 2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (5- fluorine pyridine -2- base) acetamide (60.5mg, 26% yield), is brown solid.LCMS m/z=385 [M+H]+。1H NMR (400MHz, DMSO-d6)δppm 8.56 (d, J=2.8Hz, 1H), 7.91 (s, 1H), 7.81-7.70 (m, 2H), 7.42 (s, 1H), 5.76 (s, 1H), 3.30 (s, 6H), 2.76 (q, J=7.7Hz, 2H), 1.21 (t, J=7.6Hz, 3H).
Embodiment 200
2- ((3,5- dicyano -4- ethyl -6- (4- (furans -3- ylmethyl) piperazine -1- base) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides
By 2- ((3,5- dicyano -4- ethyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides, 2, 2,2- trifluoro-acetates (describing synthesis, 215mg, 0.413mmol in 176 step 2 of embodiment) are dissolved in methylene chloride (15mL) and n,N-diisopropylethylamine (0.144mL, 826mmol) is added.Into the solution be added acetic acid (0.047mL, 0.826mmol), furans -3- formaldehyde (79mg, 0.826mmol) then is added.The reaction is stirred 30 minutes and triacetyl is added Oxygroup sodium borohydride (350mg, 1.652mmol).The reaction is stirred 18 hours at 25 DEG C and methylene chloride (30mL) is added.It will The solution saturated sodium bicarbonate aqueous solution and water washing.The organic phase is dried and concentrated with sodium sulphate.The residue is used Dichloromethane trituration is collected by filtration and dry in vacuum drying oven, obtains 2- ((3,5- dicyano -4- ethyl -6- (4- (furans -3- ylmethyl) piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides (100mg, 48% yield).LCMS m/ Z=487.3 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 1.20 (t, J=7.60Hz, 3H), 2.47 (br.s., 4H), 2.75 (q, J=7.43Hz, 2H), 3.40 (s, 2H), 3.88 (t, J=4.82Hz, 4H), 5.52 (s, 1H), 6.44-6.50 (m, 1H), 7.29-7.43 (m, 4H), 7.47-7.54 (m, 2H), 7.62 (s, 1H), 7.63-7.68 (m, 1H), 7.91 (s, 1H).
Embodiment 201:
2- ((3,5- dicyano -4- ethyl -6- ((2- morpholinoethyl) sulfenyl) pyridine -2- base) sulfenyl) -2- phenyl second Amide
By 2- ((chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-) sulfenyl) -2- phenyl-acetamides (in embodiment 52, Synthesis, 240mg, 0.67mmol are described in step 1) and thioacetic acid potassium (77mg, 0.67mmol) in N, N- dimethyl formyl Mixture in amine (20mL) stirs 0.5 hour at 20 DEG C.Then 4- (2- chloroethyl) morpholine (201mg, 1.35mmol) is added With triethylamine (0.375mL, 2.69mmol).The mixture is stirred 15 hours.Then the mixture is concentrated in vacuo, is somebody's turn to do Crude product is simultaneously further purified by column chromatography, and 2- ((3,5- dicyano -4- ethyl -6- ((2- morpholinoethyl) sulfenyl) are obtained Pyridine -2- base) sulfenyl) -2- phenyl-acetamides (25mg, 8% yield).LCMS m/z=468.1 [M+H]+。1H NMR (400MHz, CD3OD) δ ppm 7.60-7.52 (m, 2H), 7.49-7.37 (m, 3H), 5.71 (s, 1H), 3.68 (dd, J= 10.0,5.4Hz, 4H), 3.64 (dd, J=13.7,6.8Hz, 1H), 3.54 (dd, J=13.7,6.7Hz, 1H), 2.95 (q, J= 7.6Hz, 2H), 2.81 (dd, J=13.1,6.3Hz, 1H), 2.73 (dd, J=13.4,6.3Hz, 1H), 2.56 (s, 4H), 1.34 (d, J=7.6Hz, 3H).
Embodiment 202
2- ((3,5- dicyano -6- (4- methyl-1,4- Diazesuberane -1- base) -4- (methylsulfany) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides
Step 1:2- amino -6- sulfydryl -4- (methylsulfany) pyridine -3,5- dimethoxy nitrile
Originally by 2- (bis- (methylsulfany) methylene) malononitrile (10g, 58.7mmol) and cyano-thioacetamide (7.06g, 70.5mmol) add in n,N-Dimethylformamide (21mL) and room temperature be added dropwise triethylamine (16.37mL, 117mmol).The mixture is stirred at room temperature 18 hours.The reaction mixture is added in the 3N hydrochloric acid of 300mL.By gained Precipitating is washed with water and is dried by filtered off with suction.Obtain 2- amino -6- sulfydryl -4- (methylsulfany) pyridine -3,5- dimethoxy nitrile (13.5g, 54.7mmol, 93% yield).LCMS m/z=222.9 [M+H]+。
Step 2:2- ((6- amino -3,5- dicyano -4- (methylsulfany) pyridine -2- base) sulfenyl) -2- phenyl-acetamides
By 2- amino -6- sulfydryl -4- (methylsulfany) pyridine -3,5- dimethoxy nitrile (3g, 12.15mmol), sodium bicarbonate The chloro- 2- phenyl-acetamides (2.5g, 14.74mmol) of (4g, 47.6mmol) and 2- are closed in n,N-Dimethylformamide (100mL) And it stirs 24 hours under nitrogen at room temperature.Water is added and filters the precipitating, obtains 2- ((6- amino -3,5- dicyano -4- (methylsulfany) pyridine -2- base) sulfenyl) -2- phenyl-acetamides (4.02g, 10.63mmol, 88% yield) LCMS m/z= 356.1[M+H]+。
Step 3:2- ((chloro- 3,5- dicyano -4- (methylsulfany) pyridine -2- base of 6-) sulfenyl) -2- phenyl-acetamides
By 2- ((6- amino -3,5- dicyano -4- (methylsulfany) pyridine -2- base) sulfenyl) -2- phenyl-acetamides (2.25g, 6.33mmol) and copper chloride (II) (1.42g, 10.56mmol) are suspended in methylene chloride (100mL).By the mixture It is heated to 40 DEG C and continues 5 minutes.2- methyl -2- nitropropane (1.351mL, 11.39mmol) is molten in acetonitrile (30mL) Liquid is added slowly in the mixture and stirs the material 60 minutes at 45 DEG C.Then it is stirred 1 hour at 50 DEG C, then at 55 DEG C Stirring 1 hour, then in 60 DEG C of stirrings and while stirring by LCMS monitoring until starting material disappears.It is cooled to room temperature and mistake Filter out solid.Filtrate is concentrated.With EtOAc (3x) and NaHCO3Saturated aqueous solution extraction.Combined organic matter is washed with brine, It is dried, filtered and is concentrated with magnesium sulfate, obtain 2- ((chloro- 3,5- dicyano -4- (methylsulfany) pyridine -2- base of 6-) sulfenyl) - 2- phenyl-acetamides (2.6g, 3.12mmol), are yellow oil, without being further purified.LCMS m/z=375.0 [M+H]+。
Step 4:2- ((3,5- dicyano -6- (4- methyl-1,4- Diazesuberane -1- base) -4- (methylsulfany) pyrrole Pyridine -2- base) sulfenyl) -2- phenyl-acetamides
By 2- ((chloro- 3,5- dicyano -4- (methylsulfany) pyridine -2- base of 6-) sulfenyl) -2- phenyl-acetamides (2.6g, It 3.12mmol) is dissolved in tetrahydrofuran (100mL) and is cooled to -40 DEG C.1- methyl-1,4- Diazesuberane (400 μ are added L, 3.19mmol) and the mixture is stirred at room temperature 150 minutes.With EtOAc (3x) and saturation NaHCO3Aqueous solution post-processing. Combined organic matter is washed with brine, yellow oil is dried, filtered and be condensed into magnesium sulfate.Purify on silica gel (80g column, 100%DCM-10%IPA is in DCM w/1%NH4In OH).Required fraction is merged and is concentrated, 833mg residue is obtained.It will The 150mg residue purifies that (80g column: 100%DCM- > 10%IPA is in DCM w/1%NH on silica gel4OH；It is washed very late It is de-).Required fraction is merged and is concentrated, 2- ((3,5- dicyano -6- (4- methyl-1,4- Diazesuberane -1- base)-are obtained 4- (methylsulfany) pyridine -2- base) sulfenyl) -2- phenyl-acetamides (99mg, 0.219mmol).LCMS m/z=453.2 [M+H ]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.92 (s, 1H) 7.45-7.57 (m, 2H) 7.27-7.45 (m, 4H) 5.50 (s, 1H) 3.77-3.99 (m, 4H) 2.57-2.78 (m, 5H) 2.46 (br.s., 1H) 2.25 (s, 3H) 1.87-2.02 (m, 2H).1 Proton does not measure.
Embodiment 203
2- ((the chloro- 4- ethyl -6- of 3,5- bis- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides
Step 1:2- ((the chloro- 4- ethyl -6- fluorine pyridine -2- base of 3,5- bis-) sulfenyl) -2- phenyl-acetamides
By 3,5- bis- chloro- 2,4,6- trifluoromethyl pyridines (2.01g, 9.95mmol) be dissolved in tetrahydrofuran (40mL) and be cooled to- 78℃.Ethylmagnesium chloride (6.2mL, 12.40mmol) is added slowly to combined solution & stir 30 minutes.Gradually it is warmed to 0 DEG C and by LCMS monitor, until starting material disappear.With EtOAc (3x) and saturation NaHCO3Aqueous solution extraction.By merging Organic matter is washed with brine, and is dried, filtered with magnesium sulfate and is carefully concentrated, and volatile yellow oil is obtained.By thioacetic acid S- (2- amino -2- oxo -1- phenylethyl) ester (synthesis, 2.291g, 10.95mmol are described in embodiment 62, step 5) It is dissolved in ethyl alcohol (40mL) and NaBH is added4(0.527g, 13.93mmol).The mixture is stirred and heated to 40 DEG C and continues 30 Minute, gas stops release.The mixture is cooled to room temperature and is added to the solution to above-mentioned yellow oil in ethanol (10mL).The mixture is stirred at room temperature 30 minutes.It is cooled to 0 DEG C and filters out solid by-product.Filtrate is condensed into Huang Color oil.(80g column, 100%DCM to 5%IPA, in DCM w/1%NH are purified on silica gel4In OH).By required fraction merge and Concentration, obtain 2- ((3,5- bis- chloro- 4- ethyl -6- fluorine pyridine -2- base) sulfenyl) -2- phenyl-acetamides (1.79g, 4.98mmol, 50% yield).LCMS m/z=359.0 [M+H]+。
Step 2:2- ((the chloro- 4- ethyl -6- of 3,5- bis- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base) pyrrole Pyridine -2- base) sulfenyl) -2- phenyl-acetamides
By 2- ((3,5- bis- chloro- 4- ethyl -6- fluorine pyridine -2- base) sulfenyl) -2- phenyl-acetamides (320mg, It 0.891mmol) adds in bottle and is dissolved in tetrahydrofuran (6mL).2- (1,4- Diazesuberane -1- base) ethyl alcohol is added (167mg, 1.158mmol) and the mixture is heated to 70 DEG C continues 20 hours.It is cooled to room temperature and the material is concentrated.It will The material purifies (C18 column, 20-70% water w/0.1%NH on Basic Gilson HPLC4OH/ acetonitrile), by required fraction Merge and be concentrated, obtains 2- ((3,5- bis- chloro- 4- ethyl -6- (4- (2- hydroxyethyl)-Isosorbide-5-Nitrae-Diazesuberane -1- base) pyrroles Pyridine -2- base) sulfenyl) -2- phenyl-acetamides (120mg, 0.248mmol, 28% yield).LCMS m/z=483.2 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.83 (s, 1H) 7.45-7.57 (m, 2H) 7.17-7.43 (m, 4H) 5.46 (s, 1H) 4.37 (t, J=5.32Hz, 1H) 3.40-3.61 (m, 6H) 2.62-2.89 (m, 6H) 2.55 (t, J=6.46 6Hz, 2H) 1.78- 1.95 (m, 2H) 1.09 (t, J=7.48Hz, 3H).
Embodiment 204
2- ((3,5- dicyano -4- ethyl -6- (hexahydropyrrolo simultaneously [3,4-b] [1,4] oxazines -6 (2H)-yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides
Step 1:6- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) hexahydropyrrolo simultaneously [3,4-b] [1,4] oxazines - 4 (4aH)-t-butyl formates
Chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile (250mg, 1.106mmol) of 2,6- bis- is dissolved in tetrahydrofuran (4mL) simultaneously Hexahydropyrrolo simultaneously [3,4-b] [Isosorbide-5-Nitrae] oxazines -4 (4aH)-t-butyl formate (252mg, 1.106mmol) is added, N is then added, N- diisopropylethylamine (0.386mL, 2.212mmol).The reaction is stirred 4 hours at 50 DEG C.The solvent is evaporated and by institute It obtains solid to be dissolved in ethyl acetate and be washed with water, be dried and concentrated with sodium sulphate.The residue is dissolved in methylene chloride (5mL) And with gradient silica gel chromatography, uses the hexane solution of 10-80% ethyl acetate as eluant, eluent, obtain 6- (6- chloro- 3,5- Dicyano -4- ethylpyridine -2- base) hexahydropyrrolo simultaneously [3,4-b] [Isosorbide-5-Nitrae] oxazines -4 (4aH)-t-butyl formate (412mg, 89% yield).LCMS m/z=418.0 [M+H]+。
Step 2:2- ((3,5- dicyano -4- ethyl -6- (hexahydropyrrolo simultaneously [3,4-b] [1,4] oxazines -6 (2H)-yl) Pyridine -2- base) sulfenyl) -2- phenyl-acetamides
Thioacetic acid S- (2- amino -2- oxo -1- phenylethyl) ester (in 62 step 5 of embodiment is described into conjunction It is dissolved in ethyl alcohol (3mL) at 268mg, 1.282mmol), is heated to 70 DEG C and NaBH is added portionwise4(52.2mg, 1.380mmol).After 3 minutes, which is added to 6- (chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-), and hexahydropyrrolo is simultaneously [3,4-b] [Isosorbide-5-Nitrae] oxazines -4 (4aH)-t-butyl formate (412mg, 0.986mmol) is in the solution in tetrahydrofuran (4mL). The reaction is heated 10 minutes at 70 DEG C and evaporates the solvent.Then the residue is dissolved in ethyl acetate and is washed with water It washs., the concentration dry with sodium sulphate and with gradient silica gel chromatography by organic phase, using the ethyl acetate of 10-70% in hexane In solution as eluant, eluent, obtain 6- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- second Yl pyridines -2- base) hexahydropyrrolo simultaneously [3,4-b] [Isosorbide-5-Nitrae] oxazines -4 (4aH)-t-butyl formate (250mg, 46% yield).LCMS M/z=549.3 [M+H]+.Then the material is stirred to 1 in room temperature in the mixture of methylene chloride (5mL) and TFA (5mL) small When.The solution is concentrated, then by residue solution saturated sodium bicarbonate aqueous solution in methylene chloride and water washing. Organic phase is dry with sodium sulphate, it is concentrated and is dried overnight at 40 DEG C, obtain 2- ((3,5- dicyano -4- ethyl -6- (hexahydro pyrroles Cough up simultaneously [3,4-b] [Isosorbide-5-Nitrae] oxazines -6 (2H)-yl) pyridine -2- base) sulfenyl) -2- phenyl-acetamides (200mg, 45% yield). LCMS m/z=449.2 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 1.05-1.35 (m, 3H), 2.50-2.61 (m, 2H), 2.70-2.80 (m, 2H), 2.85-2.96 (m, 1H), 3.40-4.05 (m, 8H), 5.67-5.65 (m, 1H), 7.21-7.45 (m, 4H), 7.50-7.57 (m, 2H), 7.94 (d, J=9.38Hz, 1H).
Embodiment 205
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (5- picoline -2- base) acetamide
Step 1:2- hydroxyl -2- (5- picoline -2- base) acetamide
Trimethyl cyanogen is added in the solution in DCM (40mL) to 5- picoline -2- formaldehyde (1.00g, 8.26mmol) Silane (1.446mL, 11.56mmol).The mixture is stirred at room temperature overnight.The mixture is concentrated, brown oil is obtained, it will It is handled 4 hours with the concentrated sulfuric acid (5mL, 94mmol), is then poured into ice the reaction mixture and is used NH4OH adjust pH to 9.The mixture and silica are concentrated, with silica gel column purification (40g column), use 0-10%MeOH/ DCM obtains 2- hydroxyl -2- (5- picoline -2- base) acetamide (1.04g, 6.26mmol, 76% yield), is yellow wax Shape solid.LCMS m/z=167.0 [M+H]+。
Step 2: methanesulfonic acid 2- amino -1- (5- picoline -2- base) -2- oxoethyl ester
To 2- hydroxyl -2- (5- picoline -2- base) acetamide (1.04g, 6.26mmol) and TEA (1.745mL, Methane sulfonyl chloride (0.585mL, 7.51mmol) 12.52mmol) is added dropwise in the pulp solution in THF (25mL).By the reaction Mixture is stirred at room temperature 3 hours, is then diluted with DCM, with water and salt water washing, uses Na2SO4Dry, concentration obtains methylsulphur Sour 2- amino -1- (5- picoline -2- base) -2- oxoethyl ester (1.49g, 6.10mmol, 97% yield) is orange wax-like Solid.LCMS m/z=245.0 [M+H]+。
Step 3:2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) -2- (5- picoline -2- base) acetamide
In ice water bath temperature, (described in embodiment 3, step 2 to chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- Synthesis, 150mg, 0.664mmol) 1- methyl-1,4- Diazesuberane are added dropwise in the solution in DMF (5mL) The solution of (0.094mL, 0.730mmol) in DMF (2mL).The mixture after ten minutes, is warming up to room temperature and stirred again by stirring It mixes 30 minutes.Then it is mixed thioacetic acid potassium (99mg, 0.863mmol) and TEA (0.277mL, 1.991mmol) to be added into the reaction Object is closed, it is stirred for 2 hours at 50 DEG C.Then by methanesulfonic acid 2- amino -1- (5- picoline -2- base) -2- oxoethyl ester (194mg, 0.796mmol) is added in the reaction solution.The reaction mixture is stirred at room temperature for the weekend.The reaction is mixed Object is diluted with water (40mL), is extracted with EtOAc (4x).Combined organic matter is washed with brine and uses Na2SO4It dries and concentrates. By the residue with silica gel chromatography (40g column, 0-100% (1%NH4OH+9%MeOH+90% DCM)/DCM), obtain 2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) -2- (5- picoline -2- base) acetamide is yellow solid.LCMS m/z=450.3 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 1.22 (t, J=7.6Hz, 3H), 1.91 (br.s., 2H), 2.24 (s, 3H), 2.29 (s, 3H), 2.40-2.49 (m, 2H), 2.52-2.57 (m, 1H), 2.58-2.70 (m, 1H), 2.77 (q, J=7.6Hz, 2H), 3.78- 3.99 (m, 4H), 5.59 (s, 1H), 7.38 (s, 1H), 7.50 (d, J=8.1Hz, 1H), 7.64 (dd, J=8.0,1.6Hz, 1H), 7.84 (s, 1H), 8.33-8.41 (m, 1H).
Embodiment 206
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (6- fluorine pyridine -2- base) acetamide
The bromo- 2- of step 1:2- (6- fluorine pyridine -2- base) acetamide
To 2- (6- fluorine pyridine -2- base) acetic acid (580mg, 3.74mmol) in DCM (20mL) in the solution of slight pulp It is added phosphorus tribromide (1M is in DCM, 4.11mL, 4.11mmol), after stirring 30 minutes, bromine (0.288mL, 5.61mmol) is added dropwise The mixture is simultaneously stirred at room temperature overnight by DCM (5mL) solution.The reaction mixture is concentrated, then by residue DCM (10mL) dilutes and NH is added dropwise4OH (2.5mL) is simultaneously stirred 1 hour.The mixture is concentrated and is used silica gel purification, it is bromo- to obtain 2- 2- (6- fluorine pyridine -2- base) acetamide (255mg, 1.094mmol, 29% yield), is brown solid.LCMS m/z= 232.9[M+H]+。
Step 2:2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) -2- (6- fluorine pyridine -2- base) acetamide
In ice water bath temperature, (described in embodiment 3, step 2 to chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- Synthesis, 150mg, 0.664mmol) 1- methyl-1,4- Diazesuberane are added dropwise in the solution in DMF (5mL) The solution of (0.094mL, 0.730mmol) in DMF (2mL).The mixture after ten minutes, is warming up to room temperature and stirred by stirring 30 minutes.Then thioacetic acid potassium (99mg, 0.863mmol) and TEA (0.277mL, 1.991mmol) reaction is added to mix It is stirred for 1 hour by object at 50 DEG C.Then by the bromo- 2- of 2- (6- fluorine pyridine -2- base) acetamide (155mg, 0.664mmol) It adds in the reaction solution.The reaction mixture is stirred at room temperature overnight, which is diluted with DCM and use water and Salt water washing, uses Na2SO4It is dried and concentrated.Residue RP-HPLC is purified into (20-50%A-CN/ water, 0.1%NH4OH It is concentrated in water) and by obtained fractions, then the residue is further purified with silica gel (40g column, 0-100% (1%NH4OH+9%MeOH+90%DCM)/DCM), obtain 2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1, 4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (6- fluorine pyridine -2- base) acetamide (108mg, 0.238mmol, 36% yield), it is pale solid.LCMS m/z=454.3 [M+H]+。1H NMR (400MHz, DMSO-d6)δppm 1.17-1.28 (m, 3H), 1.78-1.99 (m, 2H), 2.23 (s, 3H), 2.35-2.50 (m, 3H), 2.59-2.69 (m, 1H), 2.78 (q, J=7.6Hz, 2H), 3.75-3.96 (m, 4H), 5.62 (s, 1H), 7.17 (dd, J=8.1,2.5Hz, 1H), 7.51 (s, 1H), 7.58 (dd, J=7.5,2.2Hz, 1H), 7.95-8.09 (m, 2H).
Embodiment 207
2- ((3,5- dicyano -6- (4- (dimethylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- (4- fluorophenyl) acetamide
The chloro- 6- of step 1:2- (4- (dimethylamino) piperidin-1-yl) -4- ethylpyridine -3,5- dimethoxy nitrile
At 0 DEG C, to chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (in 3 step 2 of embodiment describe synthesis, 300mg, 1.327mmol) in the agitating solution in methylene chloride (5mL) be added triethylamine (0.185mL, 1.327mmol) and N, N- lupetidine -4- amine (170mg, 1.327mmol).By the reaction mixture in mutually synthermal stirring 5 minutes.This is anti- Mixture is answered to be quenched with ice cold water (50mL) and extracted with methylene chloride (2x 50mL).By combined organic layer water (2x100mL) is washed and is concentrated in vacuo, and is obtained (350mg, 76% yield), is semisolid.LCMS m/z=318.2 [M+H ]+。
Step 2:2- (4- fluorophenyl) -2- hydroxyl acetamide
At 0 DEG C, to agitating solution of 2- (4- the fluorophenyl) -2- hydroxyacetic acid (1g, 5.88mmol) in methanol (10mL) Simultaneously the reaction mixture is stirred at room temperature 5 hours for middle addition chloroacetic chloride (1.254mL, 17.63mmol).By the reaction mixture It is concentrated under reduced pressure, to remove all volatile matters.Then methanol (10mL) and ammonium hydroxide (7.0mL, 44.9mmol) are added It is stirred under nitrogen atmosphere 16 hours into the reaction mixture and by the mixture in room temperature.Under reduced pressure by the reaction mixture Then cold ethyl alcohol (5mL) is added to the roughage to remove all volatile matters by concentration.Gained mixture is stirred 5 minutes, Then it filters, obtains 2- (4- fluorophenyl) -2- hydroxyl acetamide (620mg, 62% yield), be pale solid.1H NMR (400MHz, DMSO-d6) δ ppm7.49-7.39 (m, 2H), 7.37 (bs, 1H), 7.19-7.09 (m, 3H), 6.03 (d, J= 4.7Hz, 1H), 4.85 (d, J=4.7Hz, 1H).
Step 3: methanesulfonic acid 2- amino -1- (4- fluorophenyl) -2- oxoethyl ester
At 0 DEG C, to 2- (4- fluorophenyl) -2- hydroxyl acetamide (600mg, 3.55mmol) stirring in acetonitrile (10mL) Triethylamine (0.494mL, 3.55mmol) is added in the suspension mixed and stirs the reaction mixture 10 minutes at 0 DEG C.At 0 DEG C Methane sulfonyl chloride (0.276mL, 3.55mmol) is added and slowly warms to room temperature the reaction mixture and to be stirred at room temperature 6 small When.The reaction mixture is concentrated under reduced pressure.The residue is diluted with water (10mL) and is extracted with EtOAc (2x 25mL).It will close And organic layer Na2SO4It dries, filters and is concentrated under reduced pressure.The crude material ether (15mL) is ground and filtered, is obtained Methanesulfonic acid 2- amino -1- (4- fluorophenyl) -2- oxoethyl ester (450mg, 51% yield), is faint yellow solid.1H NMR (400MHz, DMSO-d6) δ ppm 7.81 (s, 1H), 7.65-7.41 (m, 3H), 7.32-7.15 (m, 2H), 5.86 (s, 1H), 3.22 (s, 3H).
Step 4:2- ((3,5- dicyano -6- (4- (dimethylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulphur Base) -2- (4- fluorophenyl) acetamide
In room temperature, to the chloro- 6- of 2- (4- (dimethylamino) piperidin-1-yl) -4- ethylpyridine -3,5- dimethoxy nitrile (350mg, 1.005mmol) in the agitating solution in n,N-Dimethylformamide (10mL) be added thioacetic acid potassium (230mg, 2.010mmol) and by the mixture in mutually synthermal stirring 2 hours.Then potassium carbonate (278mg, 2.010mmol) and first is added Sulfonic acid 2- amino -1- (4- fluorophenyl) -2- oxoethyl ester (373mg, 1.508mmol) simultaneously stirs the reaction mixture in room temperature It mixes 16 hours.The reaction mixture is diluted with cold water (50mL) and is extracted with EtOAc (2x 35mL).By combined organic layer Use Na2SO4It dries, filters and is concentrated under reduced pressure.The crude material is purified with column chromatography, using silica gel, (100-200 mesh, uses DCM/ MeOH elution), obtain 2- ((3,5- dicyano -6- (4- (dimethylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulphur Base) -2- (4- fluorophenyl) acetamide (134mg, 27% yield) is light tan solid.LCMS m/z=467.2 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.94 (br s, 1H), 7.56 (dd, J=8.55,5.26Hz, 2H), 7.35 (br s, 1H), 7.22 (t, J=8.77Hz, 2H), 5.57 (s, 1H), 4.60 (d, J=11.84Hz, 2H), 3.17 (t, J=11.95Hz, 2H), 2.84-2.66 (m, 3H), 2.37 (br s, 6H), 1.95 (d, J=12.28Hz, 2H), 1.47 (br d, J=15.13Hz, 2H), 1.17-1.23 (m, 3H).
Embodiment 208
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (4- picoline -2- base) acetamide
Step 1:2- hydroxyl -2- (4- picoline -2- base) acetamide
Trimethyl cyanogen is added in the solution in DCM (40mL) to 4- picoline -2- formaldehyde (1.03g, 8.50mmol) Silane (1.383mL, 11.05mmol).The mixture is stirred at room temperature overnight.The reaction mixture is concentrated, brown is obtained It is handled 4 hours with the concentrated sulfuric acid (5mL, 94mmol), then pours on ice the reaction mixture and use NH by oil4OH tune Save pH to 9.The mixture is concentrated with silica gel, with silica gel column purification (40g column, 0-8%MeOH/DCM), 2- hydroxyl -2- (4- picoline -2- base) acetamide (435mg, 2.62mmol, 31% yield) is obtained, it is solid for yellow waxy Body.LCMS m/z=167.0 [M+H]+。
Step 2: methanesulfonic acid 2- amino -1- (4- picoline -2- base) -2- oxoethyl ester
To 2- hydroxyl -2- (4- picoline -2- base) acetamide (435mg, 2.62mmol) and TEA (0.730mL, Methane sulfonyl chloride (0.245mL, 3.14mmol) 5.24mmol) is added dropwise in the slurries in THF (15mL).By the reaction mixture It is stirred at room temperature overnight.The reaction mixture is diluted with DCM and water, separates each layer.Water layer is extracted with DCM (2x).It will close And organic matter be washed with brine, use Na2SO4Dry, concentration obtains methanesulfonic acid 2- amino -1- (4- picoline -2- base) -2- Oxoethyl ester (568mg, 2.325mmol, 89% yield) is brown waxy solid.LCMS m/z=245.1 [M+H]+。
Step 3:2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) -2- (4- picoline -2- base) acetamide
To chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in embodiment 3, step 2,130mg, 0.575mmol) the dropwise addition 1- methyl-1 in the solution in DMF (3.5mL), 4- Diazesuberane (0.081mL, 0.633mmol) the solution in DMF (1.5mL).It stirs after sixty minutes, then by thioacetic acid potassium (85mg, 0.748mmol) The reaction mixture is added to TEA (0.240mL, 0 1.725mmol), it is stirred for 2 hours at 50 DEG C.Then by methanesulfonic acid 2- amino -1- (4- picoline -2- base) -2- oxoethyl ester (169mg, 0.690mmol) adds in the reaction solution.It should Reaction mixture is stirred at room temperature overnight.Extremely by the reaction mixture loadingAnd with silica gel purification (24g column, 100% hexane continue 3 minutes, then 0-20%MeOH/DCM).Simultaneously by obtained fractions concentration It is ground with ethyl alcohol, obtains 2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) -2- (4- picoline -2- base) acetamide (77mg, 0.171mmol, 30% yield) is pale solid. LCMS m/z=450.2 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 1.22 (t, J=7.6Hz, 3H), 1.92 (br.s., 2H), 2.25 (s, 3H), 2.33 (s, 3H), 2.46 (br.s., 2H), 2.56 (br.s., 1H), 2.66 (d, J= 13.4Hz, 1H), 2.78 (q, J=7.6Hz, 2 6H), 3.81-3.99 (m, 4H), 5.58 (s, 1H), 7.20 (d, J=4.3Hz, 1H), 7.38 (s, 1H), 7.45 (s, 1H), 7.84 (s, 1H), 8.40 (d, J=5.1Hz, 1H).
Embodiment 209
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (3-Methoxy Pyridine -2- base) acetamide
Step 1:2- hydroxyl -2- (3-Methoxy Pyridine -2- base) acetamide
Trimethyl is added in the solution in DCM (40mL) to 3-Methoxy Pyridine -2- formaldehyde (1.07g, 7.57mmol) Cyanogen silane (1.231mL, 9.84mmol).The mixture is stirred at room temperature overnight.The mixture is concentrated, brown oil is obtained, It is handled 4 hours with the concentrated sulfuric acid (5mL, 94mmol), then the reaction mixture is poured into ice and uses NH4OH adjusts pH To 9.The mixture is usedConcentration, with silica gel column purification (40g column, 0-6%MeOH/DCM), 2- hydroxyl -2- (3-Methoxy Pyridine -2- base) acetamide (983mg, 5.40mmol, 71% yield) is obtained, is beige solid. LCMS m/z=183.0 [M+H]+。
Step 2: methanesulfonic acid 2- amino -1- (3-Methoxy Pyridine -2- base) -2- oxoethyl ester
To 2- hydroxyl -2- (3-Methoxy Pyridine -2- base) acetamide (980mg, 5.38mmol) and TEA (1.500mL, Methane sulfonyl chloride (0.503mL, 6.46mmol) 10.76mmol) is added dropwise in the slurries in THF (25mL).The reaction is mixed Object is stirred at room temperature 3 hours.Methylene chloride (10mL) and n,N-Dimethylformamide (5.00mL) are added into the reaction mixture, It is stirred for 1 hour.The reaction mixture is diluted with more DCM and used water and salt water washing, uses Na2SO4It is dry, it is dense Contracting, obtaining methanesulfonic acid 2- amino -1- (3-Methoxy Pyridine -2- base) -2- oxoethyl ester, (499mg, 1.917mmol, 36% are produced Rate), it is light yellow solid.LCMS m/z=261.0 [M+H]+。
Step 3:2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) -2- (3-Methoxy Pyridine -2- base) acetamide
To chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in embodiment 3, step 2,130mg, 1- methyl-1,4- Diazesuberane (0.081mL, 0.633mmol) 0.575mmol) are added dropwise in the solution in DMF (3mL) Solution in DMF (1mL).Stirring after sixty minutes, by thioacetic acid potassium (92mg, 0.805mmol) and TEA (0.240mL, It 1.725mmol) adds in the reaction mixture, it is stirred for 2 hours at 50 DEG C.Then by methanesulfonic acid 2- amino -1- (3- first Oxygroup pyridine -2- base) -2- oxoethyl ester (150mg, 0.575mmol) adds in the reaction solution.The reaction mixture is existed It is stirred overnight at room temperature.Extremely by the mixture loadingAnd with silica gel purification (24g column), it uses 100% hexane continues 5 minutes, then 0-20%MeOH/DCM.Obtained fractions are concentrated, then grind the residue with ethyl alcohol Mill, obtains 2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) - 2- (3-Methoxy Pyridine -2- base) acetamide (84mg, 0.180mmol, 31% yield), is pale solid.LCMS m/z =466.3 [M+H]+。1H NMR (400MHz, chloroform-d) δ ppm 1.34 (t, J=7.6Hz, 3H), 2.14-2.31 (m., 2H), 2.59 (br.s., 3H), 2.68-3.35 (m, 6H), 3.91 (s, 3H), 4.06 (t, J=5.7Hz, 2H), 4.22 (br.s., 2H), 5.55 (br.s., 1H), 6.15 (br.s., 1H), 7.10 (br.s., 1H), 7.25-7.32 (m, 2H), 8.21 (dd, J=4.4, 1.4Hz, 1H).
Embodiment 210
2- ((3,5- dicyano -6- (4- (dimethylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- (2,4 difluorobenzene base) acetamide
Step 1:2- (2,4 difluorobenzene base) -2- hydroxyl acetamide
It is molten in methanol (20mL) to 2- (2,4- difluorophenyl) -2- hydroxyacetic acid (2g, 10.63mmol) at 0 DEG C Chloroacetic chloride (2.268mL, 31.9mmol) is added in liquid and the mixture is stirred at room temperature 5 hours.The reaction mixture is existed The lower concentration of decompression, obtains the crude product.In room temperature, methanol (20mL) and ammonium hydroxide (14mL, 360mmol) are added thereto And the mixture is stirred 15 hours.The reaction mixture is concentrated under reduced pressure, then by the residue frozen ethanol (10mL) washing, obtains 2- (2,4- difluorophenyl) -2- hydroxyl acetamide (1.8g, 70% yield), is pale solid. LCMS m/z=187.9 [M+H]+。
Step 2: methanesulfonic acid 2- amino -1- (2,4 difluorobenzene base) -2- oxoethyl ester
In room temperature, to 2- (2,4- difluorophenyl) -2- hydroxyl acetamide (1.8g, 9.62mmol) in methylene chloride Triethylamine (4.02mL, 28.9mmol) is added in agitating solution in (18mL).After five minutes, in 0 DEG C of addition mesyl chloride (0.899mL, 11.54mmol) and gained mixture is stirred at room temperature 1 hour.Water (20mL) is added and uses the mixture DCM (2x 20mL) extraction.Combined organic layer is dried, filtered and is concentrated under reduced pressure with anhydrous sodium sulfate, methanesulfonic acid 2- ammonia is obtained Base -1- (2,4- difluorophenyl) -2- oxoethyl ester (1.6g, 57% yield), is pale solid.1H NMR (400MHz, CDCl3) δ ppm 7.45 (td, J=8.39,6.25Hz, 1H), 7.00-6.87 (m, 2H), 6.50 (bs, 1H), 6.08 (s, 1H), 5.78 (bs, 1H), 2.97 (s, 3H).
Step 3:2- ((3,5- dicyano -6- (4- (dimethylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulphur Base) -2- (2,4 difluorobenzene base) acetamide
In room temperature, to the chloro- 6- of 2- (4- (dimethylamino) piperidin-1-yl) -4- ethylpyridine -3,5- dimethoxy nitrile (in reality Apply in 207 step 1 of example and describe synthesis, 600mg, 1.888mmol) add in the solution in n,N-Dimethylformamide (10mL) Enter thioacetic acid potassium (431mg, 3.78mmol) and by gained mixture in mutually synthermal stirring 2 hours.Potassium carbonate is added (522mg, 3.78mmol) and methanesulfonic acid 2- amino -1- (2,4- difluorophenyl) -2- oxoethyl ester (501mg, 1.888mmol) And the mixture is stirred at room temperature 12 hours.The reaction mixture is diluted with ice water (50mL) and with ethyl acetate (2x 50mL) extract.Combined organic layer is dried, filtered and is concentrated in vacuo with anhydrous sodium sulfate, crude product is obtained.By the crude product Purified with column chromatography, used silica gel (100-200 mesh is eluted with 60-70% petrol ether/ethyl acetate).The pure fraction is subtracted Pressure concentration, obtains 2- ((3,5- dicyano -6- (4- (dimethylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) - 2- (2,4- difluorophenyl) acetamide (120mg, 13% yield), is Light brown solid.LCMS m/z=485.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.91 (s, 1H), 7.57 (td, J=8.77,6.58Hz, 1H), 7.47 (s, 1H), 7.39-7.30 (m, 1H), 7.13 (td, J=8.50,2.30Hz, 1H), 5.76 (s, 1H), 4.51 (d, J=14.69Hz, 2H), 3.17 (t, J=12.61Hz, 2H), 2.77 (q, J=7.53Hz, 2H), 2.47-2.39 (m, 1H), 2.21 (s, 6H), 1.85 (d, J=12.28Hz, 2H), 1.52-1.32 (m, 2H), 1.21 (t, J=7.78Hz, 3H).
Embodiment 211:
2- ((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- (5- fluorine pyridine -2- base) acetamide, formates
The chloro- 4- ethyl -6- of step 1:2- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -3,5- dimethoxy nitrile
At 0 DEG C, solution of 4- (pyrrolidin-1-yl) piperidines (1.5g, 9.72mmol) in methylene chloride (30mL) is added To chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describing synthesis, 2.198g, 9.72mmol in 3 step 2 of embodiment) With triethylamine (4.07mL, 29.2mmol) in the mixture in methylene chloride (30mL).The mixture is warmed to 25 DEG C simultaneously Stirring 12 hours.The mixture is washed with water (30mL).The organic phase is concentrated, it is then that the residue column chromatography is pure Change, using petroleum ether/EtOAc (2/1), obtain the chloro- 4- ethyl -6- of 2- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -3, 5- dimethoxy nitrile (3.6g, 92% yield).LCMS m/z=344.1 [M+H]+。
Step 2:2- ((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- (5- fluorine pyridine -2- base) acetamide, formates
At 0 DEG C, to the chloro- 4- ethyl -6- of 2- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -3,5- dimethoxy nitrile (344mg, 1.000mmol) in the solution in n,N-Dimethylformamide (10mL) be added thioacetic acid potassium (126mg, 1.100mmol).The mixture is warmed to 25 DEG C and is stirred 2 hours.The mixture is concentrated, then by the residue column Chromatogram purification obtains 4- ethyl -2- sulfydryl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyrrole using DCM/MeOH (100/1) Pyridine -3,5- dimethoxy nitrile (290mg, 85% yield).To methanesulfonic acid 2- amino -1- (5- fluorine pyridine -2- base) -2- oxoethyl ester 4- ethyl -2- sulfydryl -6- (4- (pyrrole is added in (211mg, 0.849mmol) in the solution in n,N-Dimethylformamide (3mL) Cough up alkane -1- base) piperidin-1-yl) pyridine -3,5- dimethoxy nitrile (290mg, 0.849mmol) is in n,N-Dimethylformamide (3mL) Solution.The mixture is stirred 16 hours at 25 DEG C.The mixture is concentrated, then by residue preparative-HPLC Purifying, obtains 2- ((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- (5- fluorine pyridine -2- base) acetamide, formates (110mg, 24% yield), is pale solid.LCMS m/z=494.1 [M +H]+。1H NMR (400MHz, DMSO-d6) δ ppm8.57 (s, 1H), 8.19 (s, 1H), 7.94 (s, 1H), 7.71 (m, 2H), 7.45 (s, 1H), 5.70 (s, 1H), 4.40 (d, J=12Hz, 2H), 3.26 (t, J=12Hz, 2H), 2.76 (m, 2H), 2.62 (m, 4H), 2.51 (m, 1H), 1.93 (m, 2H), 1.72 (s, 4H), 1.49 (m, 1H), 1.37 (m, 1H), 1.21 (m, 3H).
Embodiment 212
2- ((3,5- dicyano -4- ethyoxyl -6- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base) pyrrole Pyridine -2- base) sulfenyl) propionamide
Step 1:2- ((6- amino -3,5- dicyano -4- ethoxy pyridine -2- base) sulfenyl) propionamide
Thioacetic acid S- (1- amino -1- oxo propyl- 2- yl) ester (356mg, 2.419mmol) is dissolved in ethyl alcohol (40mL) And NaBH is added4(111mg, 2.93mmol).By the mixture be stirred and heated to 40 DEG C continue 30 minutes and gas stopping release It puts.The mixture is cooled to room temperature and add to chloro- 4- ethoxy pyridine -3, the 5- dimethoxy nitrile of 2- amino -6- (522mg, 2.345mmol) the solution in ethyl alcohol (20mL).The mixture is stirred at room temperature 5 hours.It is cooled to 0 DEG C and filtering, is obtained (749mg, 2.262mmol, 96% are produced 2- ((6- amino -3,5- dicyano -4- ethoxy pyridine -2- base) sulfenyl) propionamide Rate).LCMS m/z=292.1 [M+H]+。
Step 2:2- ((the chloro- 3,5- dicyano -4- ethoxy pyridine -2- base of 6-) sulfenyl) propionamide
By 2- ((6- amino -3,5- dicyano -4- ethoxy pyridine -2- base) sulfenyl) propionamide (370mg, It 1.118mmol) is dissolved in acetonitrile (20mL) and copper chloride (II) (270mg, 2.012mmol) is added.The mixture is stirred and added Heat continues 5 minutes to 45 DEG C and nitrite tert-butyl (0.24mL, 2.025mmol) is added dropwise.The mixture is heated to 45 DEG C to hold It is 1 hour continuous.It is cooled to room temperature and uses EtOAc (3x) and saturation NaHCO3Aqueous solution post-processing.By combined organic matter salt water Washing, uses MgSO4It dries, filters and is concentrated.With silica gel purification (80g column: the DCM w/1%NH of 100%DCM-5%IPA4OH is molten Liquid).Required fraction is merged and is concentrated, 2- ((chloro- 3, the 5- dicyano -4- ethoxy pyridine -2- base of 6-) sulfenyl) propionyl is obtained Amine (180mg, 0.527mmol, 47% yield).LCMS m/z=311.1 [M+H]+。
Step 3:2- ((3,5- dicyano -4- ethyoxyl -6- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- Base) pyridine -2- base) sulfenyl) propionamide
By 2- ((chloro- 3, the 5- dicyano -4- ethoxy pyridine -2- base of 6-) sulfenyl) propionamide (100mg, 0.283mmol) It is dissolved in tetrahydrofuran (6mL) and 2- (Isosorbide-5-Nitrae-Diazesuberane -1- base) ethyl alcohol (49.0mg, 0.340mmol) is added.It should Mixture stirs 30 minutes.Concentration.(80g column: 100%DCM- > 10%IPA is in DCM w/1%NH for purifying on silica gel4OH In).Required fraction is merged and is concentrated, 2- ((3,5- dicyano -4- ethyoxyl -6- (4- (2- hydroxyethyl)-Isosorbide-5-Nitrae-two is obtained Azepan -1- base) pyridine -2- base) sulfenyl) propionamide (90mg, 0.215mmol, 76% yield).LCMS m/z= 419.3[M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.69 (s, 1H) 7.24 (s, 1H) 4.49-4.59 (m, 2H) 4.35-4.45 (m, 2H) 3.76-4.00 (m, 4H) 3.47 (q, J=6.17Hz, 2H) 2.74-2.95 (m, 2H) 2.64-2.74 (m, 1H) 2.57-2.64 (m, 1H) 2.54 (t, J=6.34Hz, 2H) 1.84-1.97 (m, 2H) 1.50 (d, J=7.10Hz, 3H) 1.37 (t, J=7.10Hz, 3H).
Embodiment 213
2- ((3,5- dicyano -6- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base) -4- propoxyl group pyrrole Pyridine -2- base) sulfenyl) -2- phenyl-acetamides
The chloro- 4- propoxyl group pyridine -3,5- dimethoxy nitrile of step 1:2- amino -6-
By ethylene -1,1,2,2- tetra- formonitrile HCNs (4g, 31.2mmol) and urea (0.563g, 9.37mmol) are suspended in propyl- 1- alcohol In (40mL, 535mmol).The mixture is heated to 40 DEG C and continues 120 minutes.It is cooled to room temperature, is subsequently cooled to -78 DEG C simultaneously Stirring 30 minutes forms pale precipitation.Combined solution is filtered and washs the residue with cold ether.By the filtrate Pass through silicagel pad and uses 1:1Et2O:EtOAc elution.The product is merged with the residue, obtains 2- (dipropoxy methylene) Malononitrile (3.3g).Malononitrile (2210mg, 33.5mmol) and potassium tert-butoxide (4.07g, 36.3mmol) are suspended in 1- propyl alcohol In (175mL).The mixture is heated to 45 DEG C and continues 5 minutes.By 2- (dipropoxy methylene) malononitrile (2.2g, PrOH (10mL) solution 11.33mmol) is added slowly to the mixture and by the material reflow 3 hour.Solid is formed, by its mistake It filters and filter vacuum is concentrated and acetone (100mL) is added, the dense HCl of 20mL is then added.50 DEG C stir 130 minutes, so After be cooled to room temperature and be finally cooled to 0 DEG C.The mixture is filtered, the chloro- 4- propoxyl group pyridine -3,5- of 2- amino -6- is obtained Dimethoxy nitrile (1.53g, 6.47mmol).LCMS m/z=237.0 [M+H]+。
Step 2:2- ((6- amino -3,5- dicyano -4- propoxyl group pyridine -2- base) sulfenyl) -2- phenyl-acetamides
Thioacetic acid S- (2- amino -2- oxo -1- phenylethyl) ester (is described into conjunction in embodiment 62, step 5 Ethyl alcohol (60mL) is dissolved at 760mg, 3.63mmol) and NaBH is added4(164mg, 4.33mmol).Simultaneously by mixture stirring It is heated to 40 DEG C and continues 30 minutes, gas stops release.The mixture is cooled to room temperature and is added to the chloro- 4- third of 2- amino -6- Solution of oxygroup pyridine -3, the 5- dimethoxy nitrile (820mg, 3.46mmol) in ethyl alcohol (10mL).The mixture is stirred at room temperature 3 Hour.It is cooled to 0 DEG C and filters out product, obtain 2- ((6- amino -3,5- dicyano -4- propoxyl group pyridine -2- base) sulfenyl) - 2- phenyl-acetamides (934mg, 2.110mmol, 61% yield).LCMS m/z=368.1 [M+H]+。
Step 3:2- ((the chloro- 3,5- dicyano -4- propoxyl group pyridine -2- base of 6-) sulfenyl) -2- phenyl-acetamides
By 2- ((6- amino -3,5- dicyano -4- propoxyl group pyridine -2- base) sulfenyl) -2- phenyl-acetamides (588mg, It 1.328mmol) is dissolved in acetonitrile (25mL) and copper chloride (II) (351mg, 2.61mmol) is added.The mixture is stirred and heated Continue 5 minutes to 45 DEG C and nitrite tert-butyl (0.29mL, 2.447mmol) is added dropwise.The mixture is heated to 50 DEG C and continues 5 Hour.It is cooled to room temperature and filters out orange solids.The filtrate is concentrated and purifies (80g column: 100%DCM-5% on silica gel IPA w/1%NH in DCM4OH).Required fraction is merged and is concentrated, 2- ((chloro- 3, the 5- dicyano -4- propoxyl group pyrrole of 6- is obtained Pyridine -2- base) sulfenyl) -2- phenyl-acetamides (129mg, 0.293mmol, 22% yield).LCMS m/z=387.1 [M+H]+。
Step 4:2- ((3,5- dicyano -6- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base) third oxygen of -4- Yl pyridines -2- base) sulfenyl) -2- phenyl-acetamides
By 2- ((chloro- 3, the 5- dicyano -4- propoxyl group pyridine -2- base of 6-) sulfenyl) -2- phenyl-acetamides (65mg, 0.151mmol) be dissolved in tetrahydrofuran (5mL) and be added 2- (Isosorbide-5-Nitrae-Diazesuberane -1- base) ethyl alcohol (26.2mg, 0.181mmol).The mixture is stirred at room temperature 3 hours.Material is concentrated and purifies (40g column: 100%DCM- on silica gel 7%IPA is in DCM w/1%NH4In OH).Required fraction is merged and is concentrated, 2- ((3,5- dicyano -6- (4- (2- hydroxyl is obtained Base ethyl)-Isosorbide-5-Nitrae-Diazesuberane -1- base) -4- propoxyl group pyridine -2- base) sulfenyl) -2- phenyl-acetamides (61mg, 0.120mmol, 79% yield).LCMS m/z=495.3 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.92 (s, 1H) 4.40 (t, J of 7.45-7.54 (m, 2H) 7.30-7.43 (m, 4H) 5.50 (s, 1H) 4.46 (td, J=6.27,1.39Hz, 2H) =5.32Hz, 1H) 3.78-3.95 (m, 4H) 3.47 6 (q, J=6.08Hz, 2H) 2.70-2.89 (m, 2H) 2.57-2.70 (m, 2H) 2.52-2.56 (m, 2H) 1.89 (d, J=5.07Hz, 2H) 1.68-1.81 (m, 2H) 0.94-1.04 (m, 3H).
Embodiment 214
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (4-methoxypyridine -2- base) acetamide
Step 1:2- hydroxyl -2- (4-methoxypyridine -2- base) acetamide
Trimethyl is added in the solution in DCM (40mL) to 4-methoxypyridine -2- formaldehyde (1.01g, 7.36mmol) Cyanogen silane (1.106mL, 8.84mmol).The mixture is stirred at room temperature overnight.The mixture is concentrated, light brown is obtained It is handled 4 hours with the concentrated sulfuric acid (5mL, 94mmol), then pours into ice the reaction mixture and use NH by oil4OH tune Save pH to 9.The mixture is usedConcentration, with silica gel column purification (40g column), use 0-10% MeOH/DCM obtains 2- hydroxyl -2- (4-methoxypyridine -2- base) acetamide (748mg, 4.11mmol, 55.7% yield), For yellow solid.LCMS m/z=183.0 [M+H]+。
Step 2: methanesulfonic acid 2- amino -1- (4-methoxypyridine -2- base) -2- oxoethyl ester
To 2- hydroxyl -2- (4-methoxypyridine -2- base) acetamide (745mg, 4.09mmol) and TEA (1.140mL, Methane sulfonyl chloride (0.382mL, 4.91mmol) 8.18mmol) is added dropwise in the slurries in THF (25mL).By the reaction mixture It is stirred at room temperature overnight.The reaction mixture is diluted with DCM and water, separates each layer.Water layer is extracted with DCM (4x).It will close And organic matter be washed with brine, use Na2SO4It is dry, concentration.The residue is ground with DCM, obtains methanesulfonic acid 2- amino -1- (4-methoxypyridine -2- base) -2- oxoethyl ester (237mg, 0.911mmol, 22% yield), is pale solid. LCMS m/z=261.0 [M+H]+。
Step 3:2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) -2- (4-methoxypyridine -2- base) acetamide
To chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in embodiment 3, step 2,110mg, 1- methyl-1,4- Diazesuberane (0.069mL, 0.535mmol) 0.487mmol) are added dropwise in the solution in DMF (3mL) Solution in DMF (1.5mL).It stirs after sixty minutes, by thioacetic acid potassium (72.2mg, 0.633mmol) and TEA (0.203mL, 1.460mmol) adds to the reaction mixture, it is stirred for 1 hour at 50 DEG C.Then by methanesulfonic acid 2- amino- 1- (4-methoxypyridine -2- base) -2- oxoethyl ester (139mg, 0.535mmol) adds in the reaction solution.By the reaction Mixture is stirred at room temperature overnight.The reaction mixture reversed-phase HPLC is purified into (20-50%A-CN/ water, 0.1%NH4ON exists In water).Obtained fractions are concentrated, then by the residue methanol trituration, obtain 2- ((3,5- dicyano -4- ethyl -6- (4- Methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (4-methoxypyridine -2- base) acetamide (83mg, 0.178mmol, 37% yield), it is light yellow solid.LCMS m/z=466.3 [M+H]+。1H NMR (400MHz, DMSO- d6) δ ppm 1.22 (t, J=7.6Hz, 3H), 1.81-2.01 (m, 2H), 2.24 (s, 3H), 2.37-2.49 (m, 2H), 2.54- 2.70 (m, 2H), 2.78 (q, J=7.6Hz, 2H), 3.79-3.98 (m, 7H), 5.56 (s, 1H), 6.96 (dd, J=5.7, 2.4Hz, 1H), 7.18 (d, J=2.5Hz, 1H), 7.40 (s, 1H), 7.82 (s, 1H), 8.36 (d, J=5.8Hz, 1H).
Embodiment 215
2- ((3,5- dicyano -4- ethyl -6- (2- methyl -2,8- diaza spiro [4.5] decyl- 8- yl) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides
The chloro- 4- ethyl -6- of step 1:2- (2- methyl -2,8- diaza spiro [4.5] decyl- 8- yl) pyridine -3,5- dimethoxy nitrile
To chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in embodiment 3, step 2,350mg, 1.548mmol) in the solution in tetrahydrofuran (2mL) be added 2- methyl -2,8- diaza spiro [4.5] decane (239mg, 1.548mmol), n,N-diisopropylethylamine (0.541mL, 3.10mmol) then is added.The reaction is small in 50 DEG C of stirrings 18 When.The solvent evaporates and obtained solid water is ground and is collected by filtration.The wet solid is dissolved in methylene chloride (100mL) is washed with water and organic phase is dried, filtered and is concentrated with sodium sulphate, obtains chloro- 4- ethyl -6- (the 2- methyl-of 2- 2,8- diaza spiros [4.5] decyl- 8- yl) pyridine -3,5- dimethoxy nitrile (350mg, 66% yield).LCMS m/z=344.2 [M+H ]+。
Step 2:2- ((3,5- dicyano -4- ethyl -6- (2- methyl -2,8- diaza spiro [4.5] decyl- 8- yl) pyridine - 2- yl) sulfenyl) -2- phenyl-acetamides
(conjunction is described in embodiment 62, step 5 to thioacetic acid S- (2- amino -2- oxo -1- phenylethyl) ester NaBH is added portionwise in 70 DEG C of solution in ethyl alcohol (10mL) at 276mg, 1.32mmol)4(53.9mg, 1.425mmol).3 After minute, which is added into the chloro- 4- ethyl -6- of 2- (2- methyl -2,8- diaza spiro [4.5] decyl- 8- yl) pyridine -3,5- bis- Formonitrile HCN (350mg, 1.018mmol) is in the solution in ethyl alcohol (10mL) and tetrahydrofuran (3.0mL) and by the reaction at 70 DEG C Heating 60 minutes.By material automation gradient reverse-phase chromatogram purification, with acetonitrile-water (containing 0.1%TFA) elution (10-90% second Nitrile).Fraction containing required product is merged and the solvent portions are concentrated to remove acetonitrile.Sodium bicarbonate is added dropwise into the solution Obtained solid is simultaneously collected by filtration and is dried with sodium sulphate by saturated aqueous solution, obtains 2- ((3,5- dicyano -4- ethyl -6- (2- methyl -2,8- diaza spiro [4.5] decyl- 8- yl) pyridine -2- base) sulfenyl) (100mg, 19% produces -2- phenyl-acetamides Rate).LCMS m/z=475.3 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.92 (br.s., 1H), 7.47-7.54 (m, 2H), 7.27-7.43 (m, 5H), 5.52 (s, 1H), 3.66-3.98 (m, 4H), 2.75 (q, J=7.44Hz, 2H), 2.23- 2.34 (m, 3H), 1.53-1.75 (m, 6H), 1.20 (t, J=7.60Hz, 3H).
Embodiment 216
2- ((3,5- dicyano -6- (4- (dimethylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- (3,4- difluorophenyl) acetamide
Step 1:2- (3,4- difluorophenyl) -2- hydroxyl acetamide
At 0 DEG C, to 2- (3,4- difluorophenyl) -2- hydroxyacetic acid (2g, 10.63mmol) stirring in methanol (20mL) It mixes and chloroacetic chloride (2.268mL, 31.9mmol) is added in solution and the mixture is stirred at room temperature 5 hours.The reaction is mixed Object is concentrated under reduced pressure, to remove all volatile matters.Addition methanol (20mL) and ammonium hydroxide (14mL, 360mmol) are simultaneously anti-by this Mixture is answered to stir 16 hours under room temperature under nitrogen atmosphere.The reaction mixture is concentrated under reduced pressure, cold ethyl alcohol is then added (5mL) and the mixture is stirred 5 minutes.The mixture is filtered, 2- (3,4- difluorophenyl) -2- hydroxyl acetamide is obtained (1.6g) is pale solid.LCMS m/z=186.0 [M-H]-。
Step 2: methanesulfonic acid 2- amino -1- (3,4- difluorophenyl) -2- oxoethyl ester
At 0 DEG C, to 2- (3,4- difluorophenyl) -2- hydroxyl acetamide (1.6g, 6.97mmol) at methylene chloride (20mL) In stirring suspension in be added triethylamine (1.944mL, 13.95mmol).The reaction mixture is stirred 10 points at 0 DEG C Clock.Then methane sulfonyl chloride (0.598mL, 7.67mmol) is added.The reaction mixture is slowly warmed to room temperature and to stir 6 small When.The reaction mixture is concentrated under reduced pressure, diluted with water (50mL) and is extracted with EtOAc (2x 60mL).By having for merging Machine layer passes through anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure.The crude compound is ground with ether (25mL), is filtered and dry It is dry, methanesulfonic acid 2- amino -1- (3,4- difluorophenyl) -2- oxoethyl ester (1g, 54% yield) is obtained, is pale yellow colored solid Body.1H NMR (400MHz, DMSO-d6): δ ppm 7.83 (s, 1H), 7.71-7.43 (m, 3H), 7.35 (dt, J=8.6, 2.9Hz, 1H), 5.88 (s, 1H), 3.26 (s, 3H).
Step 3:2- ((3,5- dicyano -6- (4- (dimethylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulphur Base) -2- (3,4- difluorophenyl) acetamide
In room temperature, to the chloro- 6- of 2- (4- (dimethylamino) piperidin-1-yl) -4- ethylpyridine -3,5- dimethoxy nitrile (in reality Apply in 207 step 1 of example and describe synthesis, 500mg, 1.417mmol) agitating solution in n,N-Dimethylformamide (20mL) Simultaneously the reaction mixture is stirred at room temperature 2 hours for middle addition thioacetic acid potassium (324mg, 2.83mmol).Then carbonic acid is added Potassium (392mg, 2.83mmol), then be added methanesulfonic acid 2- amino -1- (3,4- difluorophenyl) -2- oxoethyl ester (413mg, 1.558mmol), which is stirred at room temperature 16 hours.The reaction mixture is quenched with cold water (50mL) and is used in combination EtOAc (2x 100mL) extraction.By combined organic layer Na2SO4It dries, filters and is concentrated under reduced pressure.By residue column color Spectrum purifying, uses silica gel (100-200 mesh, eluted with 10%MeOH/DCM).By the obtained solid second of 50% ethyl acetate Ethereal solution washing, filtering and vacuum drying, obtain 2- ((3,5- dicyano -6- (4- (dimethylamino) piperidin-1-yl) -4- second Yl pyridines -2- base) sulfenyl) -2- (3,4- difluorophenyl) acetamide (130mg, 19% yield).LCMS m/z=485.2 [M+H ]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.98 (s, 1H), 7.62-7.53 (m, 1H), 7.51-7.36 (m, 3H), 5.59 (s, 1H), 4.55 (br d, J=10.74Hz, 2H), 3.24-3.14 (m, 2H), 2.76 (q, J=7.60Hz, 2H), 2.53- 2.51 (m, 1H), 2.37-2.19 (m, 6H), 1.89 (br s, 2H), 1.49-1.30 (m, 2H), 1.20 (t, J=7.67Hz, 3H)。
Embodiment 217
1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperazine Pyridine -4- formamide
Step 1:1- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) piperidines -4- formamide
At 0 DEG C, to chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (in 3 step 2 of embodiment describe synthesis, 1g, 4.42mmol) addition piperidines -4- formamide (0.566g, 4.42mmol) in the agitating solution in methylene chloride (15mL), Then triethylamine (1.847mL, 13.25mmol) is added.The reaction mixture is stirred at room temperature 8 hours.The reaction is mixed Object is concentrated under reduced pressure, and is diluted with water (50mL) and is extracted with DCM (2x 80mL).By combined organic layer anhydrous Na2SO4It is dry It is dry, it filters and is concentrated under reduced pressure.Gained crude material is ground with ether (25mL), filtering and drying obtain 1- (6- chloro- 3,5- Dicyano -4- ethylpyridine -2- base) piperidines -4- formamide (800mg, 55% yield) is light tan solid.LCMS m/z =318.0 [M+H]+。
Step 2:1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) piperidines -4- formamide
In room temperature, to 1- (chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-) piperidines -4- formamide (500mg, 1.496mmol) in the agitating solution in n,N-Dimethylformamide (20mL) be added thioacetic acid potassium (342mg, 2.99mmol) and by the reaction mixture it is stirred at room temperature 2 hours.It is added potassium carbonate (413mg, 2.99mmol), is then added Methanesulfonic acid 2- amino -2- oxo -1- phenylethylester (describing synthesis, 527mg, 2.244mmol in 3 step 5 of embodiment) And the reaction mixture is stirred at room temperature 16 hours.The reaction mixture is quenched with cold water (50mL) and with EtOAc (2x 100mL) extract.By combined organic layer Na2SO4It dries, filters and is concentrated under reduced pressure.The crude material is purified with column chromatography, Using silica gel (100-200 mesh, eluted with DCM/MeOH), 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl)-is obtained 3,5- dicyano -4- ethylpyridine -2- bases) piperidines -4- formamide (109mg, 15% yield) is light tan solid.LCMS M/z=449.2 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.90 (s, 1H), 7.55-7.49 (m, 2H), 7.42- 7.27 (m, 5H), 6.82 (br s, 1H), 5.53 (s, 1H), 4.57-4.46 (m, 2H), 3.26-3.14 (m, 2H), 2.81-2.69 (m, 2H), 2.47-2.41 (m, 1H), 1.85 (br d, J=14.03Hz, 2H), 1.68-1.56 (m, 2H), 1.24-1.17 (m, 3H)。
Embodiment 218:
2- ((3,5- dicyano -6- ((2- (dimethylamino) ethyl) sulfenyl) -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides
By 2- ((chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-) sulfenyl) -2- phenyl-acetamides (in embodiment 52, Synthesis, 220mg, 0.62mmol are described in step 1) and thioacetic acid potassium (74mg, 0.65mmol) mixing in DMF (20mL) Object is closed to stir 0.5 hour at 20 DEG C.Then the chloro- N of 2-, N- dimethyl amine (332mg, 3.08mmol) and triethylamine is added (0.344mL, 2.47mmol).The mixture is stirred for 13.5 hours.The reaction mixture is allocated in ethyl acetate and water Between.The organic phase is dried, filtered and is concentrated in vacuo with anhydrous sodium sulfate, the crude product is obtained and is purified with column chromatography, obtained To 2- ((3,5- dicyano -6- ((2- (dimethylamino) ethyl) sulfenyl) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide (110mg, 42% yield).LCMS m/z=426.2 [M+H]+。1H NMR (400MHz, CDCl3) δ ppm 8.09 (s, 1H), 7.55-7.47 (m, 2H), 7.42-7.33 (m, 3H), 5.80 (s, 1H), 5.56 (s, 1H), 3.82-3.71 (m, 1H), 3.16 (dd, J=12.1,5.5Hz, 1H), 2.93 (m, 3H), 2.60 (d, J=5.8Hz, 1H), 2.37 (s, 6H), 1.32 (t, J =7.6Hz, 3H).
Embodiment 219
2- ((3,5- dicyano -6- ((3S, 4R) -3,4- dihydroxy pyrrolidine -1- base) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides
Step 1:2,5- dihydro -1H- pyrroles's -1- t-butyl formate
To 2, the 5- dihydro -1H- pyrroles (5g, 72.4mmol) in 0 DEG C of stirred under nitrogen in methylene chloride (50mL) Triethylamine (11.09mL, 80mmol) is added in suspension, di-tert-butyl dicarbonate (19.95mL, 87mmol) then is added.It will The reaction mixture stirs 2 hours at 25 DEG C.It is extracted by the reaction mixture down to water (100mL) and with DCM (3x 100mL). Combined organic layer is washed with water (2x 50mL), is dried, filtered and is evaporated in vacuo with sodium sulphate, obtain raw product 2,5- Dihydro -1H- pyrroles -1- t-butyl formate (10g), is weak yellow liquid.1H NMR (400MHz, CDCl3)δppm 5.83– 5.70 (m, 2H), 4.18-4.04 (m, 4H), 1.48 (s, 9H).
Step 2:(3R, 4S) -3,4- dihydroxy pyrrolidine -1- t-butyl formate
Solution of 2, the 5- dihydro -1H- pyrroles -1- t-butyl formate (9g, 38.7mmol) in acetone (80mL) is added dropwise It simultaneously will be warm into the mixture of NMO (4.98g, 42.5mmol), osmium tetroxide (0.607mL, 1.933mmol) and water (80mL) Degree is maintained at 0 DEG C.The reaction mixture is stirred at room temperature 16 hours.The reaction mixture is concentrated to remove the acetone, so After (3x 250mL) is extracted with ethyl acetate.By combined organic layer water (2x 100mL) and aqueous salt solu-tion, Na is used2SO4 It dries, filters and is concentrated.By the crude material with silica gel chromatography (100-200 mesh), is eluted, obtained with 100%EtOAc (3R, 4S) -3,4- dihydroxy pyrrolidine -1- t-butyl formate (8g), is light brown liquid.LCMS m/z=202.0 [M- H]-。
Step 3:(3R, 4S)-pyrrolidines -3,4- glycol, hydrochloride
At 0 DEG C, disliked to (3R, 4S) -3,4- dihydroxy pyrrolidine -1- t-butyl formate (1g, 4.36mmol) in Isosorbide-5-Nitrae-two HCl (Isosorbide-5-Nitrae-dioxane of 4M, 1.1mL) is added in solution in alkane (10mL).The reaction mixture is stirred 2 at 27 DEG C Hour.The solvent is evaporated and grinds obtained solid ether (2x 20mL), filtering and vacuum drying obtain (3R, 4S)- Pyrrolidines -3,4- glycol, hydrochloride (450mg, 74.0% yield), is light tan solid.1H NMR (400MHz, DMSO-d6) δ 9.27 (bs, 2H), 5.32 (s, 2H), 4.07 (s, 2H), 3.20 (dd, J=11.6,5.2Hz, 2H), 2.95 (dd, J=11.7, 4.7Hz, 2H).
The chloro- 6- of step 4:2- ((3S, 4R) -3,4- dihydroxy pyrrolidine -1- base) -4- ethylpyridine -3,5- dimethoxy nitrile
To (3R, 4S)-pyrrolidines -3,4- glycol in 0 DEG C of stirred under nitrogen, hydrochloride (339mg, 2.431mmol) exists Triethylamine (0.616mL, 4.42mmol) is added in solution in methylene chloride (10mL).The reaction mixture is stirred at 0 DEG C 10 minutes.Then it (is described in 3 step 2 of embodiment in the chloro- 4- ethylpyridine -3,5- dimethoxy nitrile of mutually synthermal addition 2,6- bis- Synthesis, 500mg, 2.210mmol).The reaction is stirred 2 hours at 27 DEG C.By the reaction mixture down to ice cold water It (50mL) and is extracted with DCM (3x 50mL), combined organic layer is washed with water (2x 50mL), uses Na2SO4Dry, filter and Evaporation, obtain the chloro- 6- of 2- ((3S, 4R) -3,4- dihydroxy pyrrolidine -1- base) -4- ethylpyridine -3,5- dimethoxy nitrile (600mg, 91% yield), it is light tan solid.LCMS m/z=293.0 [M+H]+。
Step 5:2- ((3,5- dicyano -6- ((3S, 4R) -3,4- dihydroxy pyrrolidine -1- base) -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides
Nitrogen at room temperature, to the chloro- 6- of 2- ((3S, 4R)-3,4- dihydroxy pyrrolidine-1- base) ethylpyridine-3-4-, Thioacetic acid potassium is added in the solution in n,N-Dimethylformamide (5mL) in 5- dimethoxy nitrile (500mg, 1.684mmol) (385mg, 3.37mmol).The suspension is stirred at room temperature 2 hours.Then 0 DEG C of addition potassium carbonate (465mg, 3.37mmol), methanesulfonic acid 2- amino -2- oxo -1- phenylethylester is then added and (describes conjunction in 3 step 5 of embodiment At 593mg, 2.53mmol).The reaction mixture is stirred 16 hours at 27 DEG C.By the reaction mixture down to ice cold water It (25mL) and is extracted with ethyl acetate (3x 50mL).Combined organic layer is dried, filtered and is evaporated in vacuo with sodium sulphate.It will Raw product obtains 2- ((3,5- dicyano -6- with silica gel chromatography (100-200 mesh, with 100% ethyl acetate elute) ((3S, 4R) -3,4- dihydroxy pyrrolidine -1- base) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides (180mg, 25% Yield), it is light tan solid.LCMS m/z=424.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm7.91 (s, 1H), 7.55-7.47 (m, 2H), 7.42-7.28 (m, 3H), 7.26 (s, 1H), 5.60 (s, 1H), 5.12 (br s, 2H), 4.13 (br s, 2H), 4.05-3.86 (m, 2H), 3.78-3.59 (m, 2H), 2.74 (q, J=7.67Hz, 2H), 1.20 (t, J= 7.6Hz, 3H).
Embodiment 220
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (3- fluorine pyridine -2- base) acetamide
Step 1:2- (3- fluorine pyridine -2- base) -2- hydroxyl acetamide
Trimethyl is added in the solution in methylene chloride (40mL) to 3- fluorine pyridine-2-formaldehyde (1.0g, 7.99mmol) Cyanogen silane (1.300mL, 10.39mmol).The mixture is stirred at room temperature overnight.The mixture is concentrated, brown oil is obtained, By it with dense H2SO4(5mL, 94mmol) is handled 4 hours, is then poured into ice the reaction mixture and is used NH4OH adjusts pH To 9.The reaction mixture is usedConcentration, with silica gel column purification (40g column), use 0-10% MeOH/DCM obtains 2- (3- fluorine pyridine -2- base) -2- hydroxyl acetamide (1.21g, 7.11mmol, 89% yield), is greyish white Color solid.LCMS m/z=171.0 [M+H]+。
Step 2: methanesulfonic acid 2- amino -1- (3- fluorine pyridine -2- base) -2- oxoethyl ester
To 2- (3- fluorine pyridine -2- base) -2- hydroxyl acetamide (1.21g, 7.11mmol) and TEA (1.982mL, 14.22mmol) in the slurries in THF (35mL) and methylene chloride (15.0mL) be added dropwise methane sulfonyl chloride (0.665mL, 8.53mmol).The reaction mixture is stirred at room temperature for the weekend.The slurry reaction mixture is diluted with DCM and water, separation Each layer.Water layer is extracted with DCM (2x).Combined organic matter is washed with brine, Na is used2SO4Dry, it is solid to obtain yellow for concentration Body.The residue is ground with DCM, obtain methanesulfonic acid 2- amino -1- (3- fluorine pyridine -2- base) -2- oxoethyl ester (987mg, 3.98mmol, 56% yield), it is pale solid.LCMS m/z=249.0 [M+H]+。
Step 3:2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) -2- (3- fluorine pyridine -2- base) acetamide
To chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in embodiment 3, step 2,110mg, 1- methyl-1,4- Diazesuberane (0.069mL, 0.535mmol) 0.487mmol) are added dropwise in the solution in DMF (3mL) Solution in DMF (1.5mL).It stirs after sixty minutes, by thioacetic acid potassium (72.2mg, 0.633mmol) and TEA (0.203mL, 1.460mmol) is added in the reaction mixture, it is stirred for 1 hour at 50 DEG C.Then by methanesulfonic acid 2- ammonia Base -1- (3- fluorine pyridine -2- base) -2- oxoethyl ester (133mg, 0.535mmol) adds in the reaction solution.The reaction is mixed Object is closed to be stirred at room temperature overnight.By the reaction mixture with silica gel purification (24g column, uses 0-20% MeOH/DCM is as eluant, eluent).Obtained fractions are concentrated, then by the residue methanol trituration, obtain 2- ((3,5- dicyan Base -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (3- fluorine pyridine -2- base) second Amide (67mg, 0.148mmol, 30% yield), is pale solid.LCMS m/z=454.2 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 1.23 (t, J=7.6Hz, 3H), 2.03 (br.s, 2H), 2.30 (s, 3H), 2.40 (br.s, 2H), 2.77-2.82 (m, 2H), 3.09 (d, J=6.6Hz, 2H), 3.79-4.10 (m, 4H), 5.96 (s, 1H), 6 7.51 (quin, J=4.2Hz, 2H), 7.74 (s, 1H), 7.78-7.86 (m, 1H), 8.43 (d, J=4.8Hz, 1H).
Embodiment 221
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (5- methoxypyridine -2- base) acetamide
Step 1:2- hydroxyl -2- (5- methoxypyridine -2- base) acetamide
Three are added in the solution in methylene chloride (40mL) to 5- methoxypyridine -2- formaldehyde (1.0g, 7.29mmol) Methyl cyanide silane (1.095mL, 8.75mmol).The mixture is stirred at room temperature overnight.The mixture is concentrated, brown is obtained Oil.By above-mentioned crude product with dense H2SO4It handles (5mL, 94mmol) 4 hours, then the reaction mixture is poured into ice and used NH4OH adjusts pH to 9.The reaction mixture is usedConcentration, with silica gel column purification (40g Column), using 0-10%MeOH/DCM, obtain 2- hydroxyl -2- (5- methoxypyridine -2- base) acetamide (1.09g, 5.98mmol, 82% yield), it is beige solid.LCMS m/z=183.0 [M+H]+。
Step 2: methanesulfonic acid 2- amino -1- (5- methoxypyridine -2- base) -2- oxoethyl ester
To 2- hydroxyl -2- (5- methoxypyridine -2- base) acetamide (1.09g, 5.98mmol) and TEA (1.668mL, Methane sulfonyl chloride (0.559mL, 7.18mmol) 11.97mmol) is added in the pulp solution in THF (35mL), by the reaction Mixture is stirred at room temperature overnight.The reaction mixture is diluted with DCM and water, separates each layer.Water layer is extracted with DCM (4x) It takes.Combined organic matter is washed with brine, Na is used2SO4It is dry, concentration.The residue is ground with DCM, obtains methanesulfonic acid 2- Amino -1- (5- methoxypyridine -2- base) -2- oxoethyl ester (533mg, 2.048mmol, 34% yield), it is solid for yellow Body.LCMS m/z=261.0 [M+H]+。
Step 3:2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) -2- (5- methoxypyridine -2- base) acetamide
To chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in embodiment 3, step 2,110mg, 0.487mmol) 1- methyl-1 is added dropwise in the solution in DMF (3mL), and 4- Diazesuberane (0.069mL, 0.535mmol) exists Solution in DMF (1.5mL).Stirring after sixty minutes, by thioacetic acid potassium (72.2mg, 0.633mmol) and TEA (0.203mL, The reaction mixture 1.460mmol) is added to, is stirred for 3 hours.Then by methanesulfonic acid 2- amino -1- (5- methoxyl group pyrrole Pyridine -2- base) -2- oxoethyl ester (139mg, 0.535mmol) adds in the reaction solution.The reaction mixture is stirred in room temperature It mixes overnight.The slurry reaction mixture water (40mL) is diluted and stirred 20 minutes.The solid is filtered and is used methanol trituration, Obtain 2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (5- methoxypyridine -2- base) acetamide (85mg, 0.183mmol, 38% yield), is pale solid.LCMS m/z= 466.3[M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 1.22 (t, J=7.6Hz, 3H), 1.87-1.98 (m, 2H), 2.24 (s, 3H), 2.41-2.49 (m, 2H), 2.54-2.59 (m, 1H), 2.60-2.69 (m, 1H), 2.77 (q, J=7.4Hz, 2H), 3.83 (s, 3H), 3.84-3.98 (m, 4H), 5.58 (s, 1H), 7.34-7.46 (m, 2H), 7.55 (d, J=8.6Hz, 1H), 7.83 (s, 1H), 8.25 (d, J=2.5Hz, 1H).
Embodiment 222:
2- ((3,5- dicyano -4- ethyl -6- (4- (1- hydroxy-2-methyl propyl- 2- yl) piperazine -1- base) pyridine -2- Base) sulfenyl) -2- (4- fluorophenyl) acetamide
The chloro- 4- ethyl -6- of step 1:2- (4- (1- hydroxy-2-methyl propyl- 2- yl) piperazine -1- base) pyridine -3,5- diformazan Nitrile
At 0 DEG C, to 2- methyl -2- (piperazine -1- base) propyl- 1- alcohol hydrochloride (691mg, 2.99mmol) in methylene chloride Triethylamine (1.136mL, 8.15mmol) and 2 is added in solution in (5mL), chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 6- bis- (describing synthesis, 615mg, 2.72mmol in 3 step 2 of embodiment).The reaction mixture is stirred 2 hours at 27 DEG C.It will The reaction mixture is quenched with ice cold water (50mL) and is extracted with DCM (3x 50mL).By combined organic layer with water (2x50mL) Washing, uses Na2SO4It dries, filters and is concentrated in vacuo, obtain the chloro- 4- ethyl -6- of 2- (4- (1- hydroxy-2-methyl propyl- 2- yl) piperazine Piperazine -1- base) pyridine -3,5- dimethoxy nitrile (800mg) is pale solid.LCMS m/z=348.1 [M+H]+。
Step 2:2- ((3,5- dicyano -4- ethyl -6- (4- (1- hydroxy-2-methyl propyl- 2- yl) piperazine -1- base) pyrrole Pyridine -2- base) sulfenyl) -2- (4- fluorophenyl) acetamide
In room temperature, (retouched in 207 step 3 of embodiment to methanesulfonic acid 2- amino -1- (4- fluorophenyl) -2- oxoethyl ester State synthesis, 604mg, 2.150mmol) thioacetic acid potassium is added in the solution in n,N-Dimethylformamide (10mL) (327mg, 2.87mmol).The reaction mixture is stirred at room temperature 2 hours.Then in mutually synthermal addition potassium carbonate (396mg, 2.87mmol) and the reaction is stirred 2 hours.Hereafter, by the chloro- 4- ethyl -6- of 2- (4- (1- hydroxy-2-methyl propyl- 2- yl) piperazine -1- base) pyridine -3,5- dimethoxy nitrile (500mg, 1.433mmol) room temperature be added and by the reaction mixture in room Temperature stirring 16 hours.The reaction mixture is quenched with ice water (12mL) and is extracted with ethyl acetate (30mL).By the merging Organic matter is dried, filtered and is concentrated with sodium sulphate.By raw product silica gel chromatography (100-200 mesh, with 2-3% first The DCM solution of alcohol elutes), Light brown solid is obtained, it is washed with mixture (30mL) of 70% ethyl acetate in ether, Filtering and drying, obtain 2- ((3,5- dicyano -4- ethyl -6- (4- (1- hydroxy-2-methyl propyl- 2- yl) piperazine -1- base) pyrrole Pyridine -2- base) sulfenyl) -2- (4- fluorophenyl) acetamide (250mg, 34% yield).LCMS m/z=497.2 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.90 (s, 1H), 7.60-7.49 (m, 2H), 7.34 (s, 1H), 7.22 (t, J=8.77Hz, 2H), 5.56 (s, 1H), 4.34 (br s, 1H), 3.85 (br s, 4H), 3.31 (br d, J=5.26Hz, 2H), 2.75 (q, J= 7.53Hz, 2H), 2.69-2.52 (m, 4H), 1.20 (t, J=7.6Hz, 3H), 1.09-0.78 (m, 6H).
Embodiment 223
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (3- (trifluoromethyl) phenyl) acetamide
Step 1:2- hydroxyl -2- (3- (trifluoromethyl) phenyl) acetamide
At 20 DEG C, 2- is added dropwise to solution of the CDI (324mg, 1.999mmol) in n,N-Dimethylformamide (0.5mL) Hydroxyl -2- (3- (trifluoromethyl) phenyl) acetic acid (220mg, 0.999mmol) is molten in n,N-Dimethylformamide (0.5mL) Liquid.Then by the reaction mixture 20 DEG C stir 1 hour, at this time by the mixture add to ammonium hydroxide (2.6mL, 20.03mmol) stirred simultaneously at 20 DEG C.Then the reaction mixture is stirred overnight mutually synthermal.It is stirred at room temperature overnight Afterwards, which is concentrated and resulting materials reversed-phase HPLC is purified into (Gilson, 30mm Gemini column, NH4OH changes Property agent), it obtains 2- hydroxyl -2- (3- (trifluoromethyl) phenyl) acetamide (95mg, 0.433mmol), is faint yellow solid. LCMS m/z=220 [M+H]+。
Step 2: methanesulfonic acid 2- amino -2- oxo -1- (3- (trifluoromethyl) phenyl) ethyl ester
At 0 DEG C, to 2- hydroxyl -2- (3- (trifluoromethyl) phenyl) acetamide (95mg, 0.433mmol), DIEA Methane sulphur is added in (0.091mL, 0.520mmol) and DMAP (5mg, 0.041mmol) in the solution in methylene chloride (2.0mL) Acyl chlorides (0.034mL, 0.433mmol).Then the reaction mixture is warmed to 20 DEG C and is stirred overnight mutually synthermal.It should Reaction mixture dilutes with DCM and uses 1N HCl (2x), saturated brine (1x), then water washing.Then organic layer is dry (MgSO4) and concentration, obtain methanesulfonic acid 2- amino -2- oxo -1- (3- (trifluoromethyl) phenyl) ethyl ester (128mg, It 0.431mmol), is orange glue.LCMS m/z=298 [M+H]+。
Step 3:2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) -2- (3- (trifluoromethyl) phenyl) acetamide
In room temperature, to 4- ethyl -2- sulfydryl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -3,5- diformazan Nitrile (synthesis, 24mg, 0.080mmol are described in embodiment 69, step 1) and methanesulfonic acid 2- amino -2- oxo -1- (3- (three Methyl fluoride) phenyl) ethyl ester (49mg, 0.165mmol) is added in the suspension in n,N-Dimethylformamide (0.5mL) Et3N (0.022mL, 0.159mmol).Then the reaction mixture is stirred at room temperature overnight.The reaction mixture is filtered. The filtrate is purified into (Gilson, 30mm Gemini column, NH with reversed-phase HPLC4OH modifying agent), obtain 2- ((3,5- dicyanos- 4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (3- (trifluoromethyl) phenyl) second Amide (13mg, 0.026mmol), is brown solid.LCMS m/z=503 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.07 (s, 1H), 7.88 (s, 1H), 7.84 (d, J=7.86Hz, 1H), 7.73 (d, J=7.86Hz, 1H), 7.65 (t, J =7.73Hz, 1H), 7.48 (s, 1H), 5.67 (s, 1H), 3.76-3.96 (m, 4H), 2.77 (q, J=7.35Hz, 2H), 2.56- 2.68 (m, 2H), 2.42-2.49 (m, 2H), 2.24 (s, 3H), 1.92 (br.s., 2H), 1.21 (t, J=7.60Hz, 3H).
Embodiment 224:
2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxyl-oxethyl) piperidin-1-yl) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides
Step 1:2- (pyridin-4-yl oxygroup) ethyl alcohol
By pyridine -4 (1H) -one (10g, 105mmol), ethylene bromohyrin (15.77g, 126mmol) and K2CO3(29.1g, 210mmol) mixture in N,N-dimethylformamide (100mL) is stirred overnight at 130 DEG C.Gained mixture is cooling simultaneously Vacuum concentration.Residue MeOH is diluted into (200mL), which is filtered and be concentrated in vacuo.By the residue silicon Glue chromatogram purification, uses CH2Cl2/ MeOH elution, obtains 2- (pyridin-4-yl oxygroup) ethyl alcohol (2g, 12% yield).LCMS m/z= 140.1[M+H]+。
Step 2:2- (piperidin-4-yl oxygroup) ethyl alcohol
PtO is added in the solution in acetic acid (30mL) to 2- (pyridin-4-yl oxygroup) ethyl alcohol (1.5g, 10.78mmol)2 (500mg).By gained mixture in 60 DEG C of 0.4MPa H2It is stirred overnight.Gained mixture is filtered and is concentrated in vacuo, is obtained 2- (piperidin-4-yl oxygroup) ethyl alcohol (3g), is colorless oil.LCMS m/z=146.2 [M+H]+。
The chloro- 4- ethyl -6- of step 3:2- (4- (2- hydroxyl-oxethyl) piperidin-1-yl) pyridine -3,5- dimethoxy nitrile
To 2- (piperidin-4-yl oxygroup) ethyl alcohol (437mg, 3.01mmol) and triethylamine (913mg, 9.02mmol) two The chloro- 4- ethylpyridine -3,5- dimethoxy nitrile of 2,6- bis- is added in solution in chloromethanes (10mL) and (describes conjunction in embodiment 3 At, step 2,680mg, 3.01mmol).Gained mixture is stirred into ambient temperature overnight, then with run with approximately half of specification Similar reaction before merges.Combined material vacuum is concentrated and is passed through silica gel chromatography, with DCM/EtOAc (1/ 1) it elutes, obtains the chloro- 4- ethyl -6- of 2- (4- (2- hydroxyl-oxethyl) piperidin-1-yl) pyridine -3,5- dimethoxy nitrile (600mg).1H NMR (400MHz, DMSO-d6) δ ppm 4.61 (t, J=5.3Hz, 1H), 4.08 (m, 2H), 3.72-3.61 (m, 3H), 3.49 (m, 4H), 2.84 (q, J=7.6Hz, 2H), 2.02-1.89 (m, 2H), 1.68-1.52 (m, 2H), 1.25 (t, J=7.6Hz, 3H)。
Step 4:2- (3,5- dicyano -4- ethyl -6- (4- (2- hydroxyl-oxethyl) piperidin-1-yl) pyridine -2- base sulphur Base) -2- phenyl-acetamides
In room temperature, to the chloro- 4- ethyl -6- of 2- (4- (2- hydroxyl-oxethyl) piperidin-1-yl) pyridine -3,5- dimethoxy nitrile (334mg, 0.998mmol) in the solution in n,N-Dimethylformamide (5mL) be added thioacetic acid potassium (171mg, 1.496mmol).The mixture is stirred at room temperature 3 hours, K is then used2CO3(276mg, 1.995mmol) processing.Gained is mixed It closes object to be stirred for 1 hour in room temperature, then with methanesulfonic acid 2- amino -2- oxo -1- phenylethylester (in embodiment 3, step 5 In describe synthesis, 229mg, 0.998mmol) processing.Gained mixture is stirred at room temperature overnight, is then concentrated in vacuo, so The residue is diluted with EtOAc (50mL) afterwards.The organic phase is washed with water (10mL) and saturated brine (10mL), uses sulfuric acid Sodium is dry and is evaporated in vacuo, and obtains raw product, is brown solid.Raw product is added into preparative-HPLC column and uses Me- CN/TFA0.1% elution, obtains 2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxyl-oxethyl) piperidin-1-yl) pyridine - 2- yl) sulfenyl) -2- phenyl-acetamides (110mg, 23% yield).LCMS m/z=466.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.92 (s, 1H), 7.52 (d, J=7.2Hz, 2H), 7.42-7.31 (m, 4H), 5.53 (s, 1H), 4.60 (s, 1H), 4.12 (m, 2H), 3.69-3.57 (m, 3H), 3.50 (dt, J=8.0,3.9Hz, 4H), 2.76 (q, J=7.6Hz, 2H), 1.93 (s, 2H), 1.64-1.50 (m, 2H), 1.21 (t, J=7.6Hz, 3H).
Embodiment 225
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (2- fluorine pyridin-3-yl) acetamide
Step 1:2- (2- fluorine pyridin-3-yl) -2- hydroxyl acetamide
Trimethyl is added in the solution in methylene chloride (30mL) to 2- fluorine pyridine -3- formaldehyde (1.1g, 8.79mmol) Cyanogen silane (1.210mL, 9.67mmol).The mixture is stirred at room temperature overnight.The mixture is concentrated, brown oil is obtained, By it with dense H2SO4(5mL, 94mmol) is handled 4 hours, is then poured into ice the reaction mixture and is used NH4OH adjusts pH To 9.The reaction mixture is usedConcentration, with silica gel column purification (40g column), use 0-15% MeOH/DCM obtains 2- (2- fluorine pyridin-3-yl) -2- hydroxyl acetamide (911mg, 5.35mmol, 61% yield), is yellow Waxy solid.LCMS m/z=171.0 [M+H]+。
Step 2: methanesulfonic acid 2- amino -1- (2- fluorine pyridin-3-yl) -2- oxoethyl ester
To 2- (2- fluorine pyridin-3-yl) -2- hydroxyl acetamide (899mg, 5.28mmol) and TEA (1.473mL, Methane sulfonyl chloride (0.494mL, 6.34mmol) 10.57mmol) is added dropwise in the pulp solution in THF (30mL), by the reaction Mixture is stirred at room temperature overnight.The reaction mixture is diluted with DCM and water, separates each layer.Water layer is extracted with DCM (2x) It takes.Combined organic matter is washed with brine, Na is used2SO4It is dry, concentration.The residue is ground with DCM, obtains methanesulfonic acid 2- Amino -1- (2- fluorine pyridin-3-yl) -2- oxoethyl ester (525mg, 2.115mmol, 40% yield), is beige solid. LCMS m/z=249.0 [M+H]+。
Step 3:2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) -2- (2- fluorine pyridin-3-yl) acetamide
To chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in embodiment 3, step 2,110mg, 1- methyl-1,4- Diazesuberane (0.069mL, 0.535mmol) 0.487mmol) are added dropwise in the solution in DMF (3mL) Solution in DMF (1.5mL).It stirs after sixty minutes, by thioacetic acid potassium (72.2mg, 0.633mmol) and TEA (0.203mL, 1.460mmol) is added to the reaction mixture, is stirred for 3 hours.Then by methanesulfonic acid 2- amino -1- (2- fluorine pyridin-3-yl) -2- oxoethyl ester (133mg, 0.535mmol) adds in the reaction solution.By the reaction mixture It is stirred at room temperature overnight.The reaction mixture is diluted with water and EtOAc (3x) is used to extract.Combined organic matter is washed with salt It washs and uses Na2SO4It is dry, be concentrated and with silica gel purification (24g column), made using 10-20%MeOH/DCM For eluant, eluent.Obtained fractions are concentrated, 2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberanes-are obtained 1- yl) pyridine -2- base) sulfenyl) -2- (2- fluorine pyridin-3-yl) acetamide (101mg, 0.223mmol, 46% yield) is shallow Yellow solid.LCMS m/z=454.2 [M+H]+.1H NMR (400MHz, DMSO-d6) ppm 1.22 (t, J=7.5Hz, 3H), 1.77-1.96 (m, 2H), 2.22 (s, 3H), 2.36-2.49 (m, 3H), 2.58-2.69 (m, 1H), 2.78 (q, J=7.6Hz, 2H), 3.75-3.94 (m, 4H), 5.77 (s, 1H), 7.36-7.45 (m, 1H), 7.60 (s, 1H), 8.00-8.08 (m, 2H), 8.22 (d, J=4.8Hz, 1H).
Embodiment 228
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (6- fluorine pyridin-3-yl) acetamide
Step 1:2- (6- fluorine pyridin-3-yl) -2- hydroxyl acetamide
Three are added in the pulp solution in methylene chloride (40mL) to 6- fluorine pyridine -3- formaldehyde (1.0g, 7.99mmol) Methyl cyanide silane (1.200mL, 9.59mmol).The mixture is stirred at room temperature overnight.The slurry mix is concentrated, is obtained The wax-like oil of brown, by it with dense H2SO4(5mL, 94mmol) is handled 4 hours, then pours into the slurry reaction mixture in ice simultaneously Use NH4OH adjusts pH to 9.The mixture is filtered to remove solid, mother liquor is usedConcentration, with silica gel column purification (40g column), using 0-15%MeOH/DCM, obtain 2- (6- fluorine pyridin-3-yl) -2- hydroxyl acetamide (235mg, 1.381mmol, 17% yield), is yellow wax.LCMS m/z=170.9 [M+H]+。
Step 2: methanesulfonic acid 2- amino -1- (6- fluorine pyridin-3-yl) -2- oxoethyl ester
To 2- (6- fluorine pyridin-3-yl) -2- hydroxyl acetamide (235mg, 1.381mmol) and TEA (0.385mL, Methane sulfonyl chloride (0.129mL, 1.657mmol) 2.76mmol) is added dropwise in the pulp solution in THF (12mL).This is anti- Mixture is answered to be stirred at room temperature overnight.The reaction mixture is concentrated and use silica gel column purification (24g column, 0-10%MeOH/DCM), obtain methanesulfonic acid 2- amino -1- (6- fluorine pyridin-3-yl) -2- oxoethyl ester (288mg, 1.160mmol, 84% yield), it is pale solid.LCMS m/z=249.0 [M+H]+。
Step 3:2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) -2- (6- fluorine pyridin-3-yl) acetamide
To chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in embodiment 3, step 2,110mg, 1- methyl-1,4- Diazesuberane (0.069mL, 0.535mmol) 0.487mmol) are added dropwise in the solution in DMF (3mL) Solution in DMF (1.5mL).It stirs after sixty minutes, by thioacetic acid potassium (72.2mg, 0.633mmol) and TEA (0.203mL, 1.460mmol) adds to the reaction mixture, is stirred for 3 hours.Then by methanesulfonic acid 2- amino -1- (6- Fluorine pyridin-3-yl) -2- oxoethyl ester (121mg, 0.487mmol) adds in the reaction solution.By the reaction mixture in room Temperature is stirred overnight.By the reaction mixture with silica gel purification (24g column), use 10-20%MeOH/DCM As eluant, eluent.Obtained fractions are concentrated to and are used methanol trituration, obtain 2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1, 4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (6- fluorine pyridin-3-yl) acetamide (56mg, 0.123mmol, 25% yield), it is white solid.LCMS m/z=454.2 [M+H]+。1H NMR (400MHz, DMSO-d) δ ppm 1.21 (t, J=7.6Hz, 3H), 1.84-2.00 (m, 2H), 2.25 (s, 3H), 2.42-2.49 (m, 2H), 2.53-2.62 (m, 1H), 2.62- 2.73 (m, 1H), 2.77 (q, J=7.4Hz, 2H), 6 3.79-3.99 (m, 4H), 5.64 (s, 1H), 7.24 (dd, J=8.5, 2.7Hz, 1H), 7.52 (s, 1H), 8.00-8.13 (m, 2H), 8.36 (d, J=2.5Hz, 1H).
Embodiment 230:
3- ((6- (2- amino -2- oxo -1- phenylethyl sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (first Base) amino) propionamide
Step 1:3- ((the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) (methyl) amino) methyl propionate
In room temperature, to 3- (methylamino) methyl propionate (1g) and triethylamine (3.46g, 34.1mmol) in methylene chloride Chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- is added in solution in (30mL) and (describes conjunction in embodiment 3, step 2 At 1.930g, 8.54mmol).Gained mixture is stirred at room temperature 3 hours, is then concentrated in vacuo.The residue is added into silicon Rubber column gel column is simultaneously eluted with hexane/EtOAc (1:1), obtains 3- ((chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-) (methyl) ammonia Base) methyl propionate (350mg, 0.685mmol).LCMS m/z=307.0 [M+H]+。
Step 2:3- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) (methyl) amino) methyl propionate
To 3- ((chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-) (methyl) amino) methyl propionate (350mg, Thioacetic acid potassium (195mg, 1.712mmol) 1.141mmol) is added in the solution in n,N-Dimethylformamide (15mL). The mixture is stirred at room temperature 2 hours, K is then used2CO3(315mg, 2.282mmol) processing.By gained mixture in room temperature Then stirring 1 hour (is described with the processing of methanesulfonic acid 2- amino -2- oxo -1- phenylethylester in embodiment 3, step 5 Synthesis, 262mg, 1.141mmol).Gained mixture is stirred at room temperature overnight, is then concentrated in vacuo.The residue is used EtOAc (50mL) dilution.The organic phase is washed with water (25mL) and saturated brine (25mL), is steamed with sodium sulphate is dry with vacuum Hair, obtains raw product, is brown solid.Raw product is added into silicagel column and is eluted with hexane/EtOAc (1:3), is obtained To 3- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) ammonia Base) methyl propionate (300mg, 0.549mmol, 48% yield).LCMS m/z=438.1 [M+H]+。
Step 3:3- ((6- (2- amino -2- oxo -1- phenylethyl sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) (methyl) amino) propionamide
By 3- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) amino) methyl propionate (240mg, 0.549mmol) and NH3Mixture in MeOH (7M, 20mL) is stirred at room temperature Overnight.In second batch, by 3- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) (methyl) amino) methyl propionate (30mg, 0.069mmol) and NH3Mixture in MeOH (7M, 2mL) is in room Temperature is stirred overnight.Two reaction mixtures are merged and are concentrated in vacuo, the residue silica gel chromatography (is then used into DCM/ MeOH, 20:1 elution), obtain 3- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) (methyl) amino) propionamide (120mg).LCMS m/z=423.1 [M+H]+。1H NMR (400MHz, DMSO) δ ppm 7.94 (s, 1H), 7.58 (s, 1H), 7.51 (d, J=7.0Hz, 2H), 7.41-7.33 (m, 4H), 7.12 (s, 1H), 5.69 (s, 1H), 4.16-4.05 (m, 1H), 3.95-3.85 (m, 1H), 3.37 (s, 3H), 2.77 (d, J=7.6Hz, 2H), 1.21 (t, J= 7.6Hz, 3H).
Embodiment 231
2- ((3,5- dicyano -4- ethyl -6- (4- (oxetanyl -3- base oxygroup) piperidin-1-yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides
The chloro- 4- ethyl -6- of step 1:2- (4- (oxetanyl -3- base oxygroup) piperidin-1-yl) pyridine -3,5- two Formonitrile HCN
To 4- toluenesulfonic acid oxetanyl -3- base ester (800mg, 3.50mmol) and pyridine -4- alcohol (367mg, K 3.86mmol) is added in the mixture in N,N-dimethylformamide (10mL)2CO3(1453mg, 10.51mmol).It should Mixture is heated to 80 DEG C and stirs 12 hours.The mixture is poured into water (20mL) and is extracted with ethyl acetate (20mL x 2) It takes.Combined organic layer is concentrated, crude 4- (oxetanyl -3- base oxygroup) pyridine is obtained, by its with similar side One batch of material of method preparation merges and column chromatography (PE/EA=2/1) is used to purify, and obtains 4- (oxetanyl -3- base oxygroup) - Pyridine.Add in the solution in acetic acid (10mL) to 4- (oxetanyl -3- base oxygroup) pyridine (600mg, 3.97mmol) Enter platinum oxide (IV) (270mg, 1.191mmol).The mixture is heated under 60 DEG C of nitrogen atmospheres (4atm) and stirred 12 hours. The mixture is filtered and is concentrated, crude 4- (oxetanyl -3- base oxygroup) piperidines (600mg) is obtained, is black Glue is employed without and is further purified.At 0 DEG C, to chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (in embodiment 3 Synthesis, 863mg, 3.82mmol are described in step 2) in the solution in methylene chloride (20mL) be added TEA (2.66mL, 19.08mmol), thick material 4- (oxetanyl -3- base oxygroup) piperidines (600mg) is then added at methylene chloride (20mL) In solution.The mixture is warmed to 25 DEG C and is stirred 16 hours.The mixture is poured into water (30mL) and will be described organic It mutually separates and is concentrated, obtain residue, it is purified with column chromatography (methylene chloride), obtains the chloro- 4- ethyl -6- (4- (oxa- of 2- Cyclobutane base -3- base oxygroup) piperidin-1-yl) pyridine -3,5- dimethoxy nitrile (700mg, 2.018mmol) is brown solid.1H NMR (400MHz, CDCl3): δ ppm 4.79-4.82 (m, 2H), 4.67-4.71 (m, 3H), 4.11-4.17 (m, 2H), 3.78- 3.84 (m, 2H), 3.64-3.69 (m, 1H), 2.96-3.02 (m, 2H), 1.91-1.98 (m, 2H), 1.72-1.80 (m, 2H), 1.35-1.39 (m, 3H).
Step 2:2- ((3,5- dicyano -4- ethyl -6- (4- (oxetanyl -3- base oxygroup) piperidin-1-yl) pyrrole Pyridine -2- base) sulfenyl) -2- phenyl-acetamides
To the chloro- 4- ethyl -6- of 2- (4- (oxetanyl -3- base oxygroup) piperidin-1-yl) pyridine -3,5- dimethoxy nitrile (346mg, 0.998mmol) in the solution in n,N-Dimethylformamide (15mL) be added thioacetic acid potassium (137mg, 1.197mmol).The mixture is stirred 2 hours at 25 DEG C.Then triethylamine (0.486mL, 3.48mmol) and methanesulfonic acid is added 2- amino -2- oxo -1- phenylethylester (describing synthesis, 266mg, 1.161mmol in 3 step 5 of embodiment).This is mixed Object is closed to stir 12 hours at 25 DEG C.The mixture is concentrated to get residue, it is purified with column chromatography (methylene chloride/methanol, 100:1).By the concentration of required fraction and then by obtained solid from acetonitrile (15mL) recrystallization, 2- ((3,5- dicyano -4- are obtained Ethyl -6- (4- (oxetanyl -3- base oxygroup) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- phenyl-acetamides (100mg, 0.209mmol) is pale solid.LCMS m/z=478.1 [M+H]+。1H NMR (400MHz, DMSO-d6): δ ppm7.92 (s, 1H), 7.51-7.53 (m, 2H), 7.34-7.41 (m, 4H), 5.53 (s, 1H), 4.69-4.73 (m, 3H), 4.46 (s, 2H), 4.17-4.20 (m, 2H), 3.64-3.66 (m, 1H), 3.51-3.54 (m, 2H), 2.73-2.79 (m, 2H), 1.87-1.89 (m, 2H), 1.47-1.54 (m, 2H), 1.19-1.23 (m, 3H).
Embodiment 232
2- ((3,5- dicyano -6- (4- ((2,2- bis-fluoro ethyls) amino) -4- methyl piperidine -1- base) -4- ethyl pyrrole Pyridine -2- base) sulfenyl) -2- phenyl-acetamides
Step 1:N- (2,2- bis-fluoro ethyls) -4- methyl piperidine -4- amine
To solution of the 4- amino -4- methyl piperidine -1- benzyl formate (400mg, 1.611mmol) in acetonitrile (10mL) Middle addition n,N-diisopropylethylamine (0.844mL, 4.83mmol).The mixture is cooled to 0 DEG C and trifluoromethanesulfonic acid is added dropwise 2,2- bis-fluoro ethyls esters (414mg, 1.933mmol) stir 20 minutes simultaneously, then warm to room temperature and stir 1 hour.Then The reaction is heated 18 hours at 50 DEG C.The reaction is concentrated and ethyl acetate is added into the residue, is then washed with water. The organic phase is dry with sodium sulphate, and concentration then by residue gradient silica gel chromatography, uses ethylacetate-hexane (10-100%) elution, obtaining 4- ((2,2- bis-fluoro ethyls) amino) -4- methyl piperidine -1- benzyl formate, (184mg, 36% produces Rate).LCMS m/z=313.3 [M+H]+.To the 4- ((2,2- bis-fluoro ethyls) amino) -4- methyl piperidine -1- benzyl formate Pd/C (17mg) is added and by the mixture in 30psi hydrogen in (184mg, 0.589mmol) in the solution in ethyl alcohol (20mL) Lower oscillation 2 hours.The mixture is filtered and is concentrated, obtain N- (2,2- bis-fluoro ethyls) -4- methyl piperidine -4- amine (80mg, 28% yield).LCMS m/z=179.1 [M+H]+。
The chloro- 6- of step 2:2- (4- ((2,2- bis-fluoro ethyls) amino)-4- methyl piperidine-1- base) ethylpyridine-3-4-, 5- dimethoxy nitrile
By chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in embodiment 3, step 2,95mg, 0.421mmol), N- (2,2- bis-fluoro ethyls) -4- methyl piperidine -4- amine (75mg, 0.421mmol) and n,N-diisopropylethylamine (0.147mL, 0.842mmol) is added in tetrahydrofuran (10mL) and is heated to 55 DEG C, while being stirred 2 hours.The solvent is steamed It sends out and grinds the residue with water.The residue is dissolved in ethyl acetate, is washed with water and dry with sodium sulphate, obtains 2- Chloro- 6- (4- ((2,2- bis-fluoro ethyls) amino) -4- methyl piperidine -1- base) -4- ethylpyridine -3,5- dimethoxy nitrile (150mg, 97% yield), it is used in next step without being further purified.LCMS m/z=368.3 [M+H]+。
Step 3:2- ((3,5- dicyano -6- (4- ((2,2- bis-fluoro ethyls) amino) -4- methyl piperidine -1- base) -4- second Yl pyridines -2- base) sulfenyl) -2- phenyl-acetamides
Thioacetic acid S- (2- amino -2- oxo -1- phenylethyl) ester (is described into conjunction in embodiment 62, step 5 70 DEG C are heated in the solution in ethyl alcohol (8mL) at 0.111g, 0.530mmol) and NaBH is added portionwise4(0.022g, 0.571mmol).After ten minutes, which is added into the chloro- 6- of 2- (4- ((2,2- bis-fluoro ethyls) amino) -4- methyl piperazine Pyridine -1- base) -4- ethylpyridine -3,5- dimethoxy nitrile (0.150g, 0.408mmol) is in 70 DEG C of solution in ethyl alcohol (8mL).Again It crosses after ten minutes, which is evaporated and solid is allocated between ethyl acetate and water.The mixture is filtered and will be organic Mutually it is dried and concentrated with sodium sulphate.The residue is dissolved in a small amount of methylene chloride and with gradient silica gel chromatography, is used The hexane solution of 10-80% ethyl acetate obtains 2- ((3,5- dicyano -6- (4- ((2,2- bis-fluoro ethyls) ammonia as eluant, eluent Base) -4- methyl piperidine -1- base) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides (25mg, 12% yield).LCMS M/z=499.4 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 1.07 (s, 3H), 1.21 (t, J=8.00Hz, 3H), 1.39-1.54 (m, 2H), 1.66 (d, J=12.93Hz, 2H), 1.91-1.98 (m, 1H), 2.75 (q, J=7.35Hz, 2H), 2.80-2.94 (m, 2H), 3.62-3.76 (m, 2H), 4.01-4.10 (m, 2H), 5.53 (s, 1H), 5.96 (tt, J=60.00, 4.00Hz, 1H), 7.30-7.42 (m, 4H), 7.48-7.56 (m, 2H), 7.93 (s, 1H).
Embodiment 233
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (4- (trifluoromethyl) phenyl) acetamide
Step 1:2- hydroxyl -2- (4- (trifluoromethyl) phenyl) acetamide
At 20 DEG C, it is added dropwise in the solution in n,N-Dimethylformamide (0.5mL) to CDI (324mg, 1.999mmol) 2- hydroxyl -2- (4- (trifluoromethyl) phenyl) acetic acid (220mg, 0.999mmol) is in n,N-Dimethylformamide (0.5mL) Solution.Then by the reaction mixture 20 DEG C stir 1 hour, at this time by the mixture add to ammonium hydroxide (2.6mL, In 20.03mmol), while being stirred at 20 DEG C.Then the reaction mixture is stirred overnight mutually synthermal.It is stirred at 20 DEG C After night, which is concentrated and resulting materials reversed-phase HPLC is purified into (Gilson, 30mm Gemini column, NH4OH Modifying agent), 2- hydroxyl -2- (4- (trifluoromethyl) phenyl) acetamide (87mg) is obtained, is pale solid.LCMS m/z= 220[M+H]+。
Step 2: methanesulfonic acid 2- amino -2- oxo -1- (4- (trifluoromethyl) phenyl) ethyl ester
In room temperature, to 2- hydroxyl -2- (4- (trifluoromethyl) phenyl) acetamide (82mg, 0.374mmol), DIEA Methane sulphur is added in (0.078mL, 0.449mmol) and DMAP (5mg, 0.041mmol) in the solution in methylene chloride (2.0mL) Acyl chlorides (0.035mL, 0.449mmol).Then the reaction mixture is stirred in the temperature for the weekend.By additional 0.5eq's Methane sulfonyl chloride is added in the reaction mixture and is stirred for 24 hours by it in room temperature.The reaction mixture is diluted with DCM And with 1N HCl (2x), saturated brine (1x), then water washing.Then by the dry (MgSO of organic layer4) and concentration, it is thick to obtain this Product.Raw product normal-phase chromatography is purified into (Biotage Isolera, 10g SNAP ULTRA column, DCM/MeOH 0- 10%) methanesulfonic acid 2- amino -2- oxo -1- (4- (trifluoromethyl) phenyl) ethyl ester (68mg), is obtained, it is solid for canescence Body.LCMS m/z=298 [M+H]+。
Step 3:2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) -2- (4- (trifluoromethyl) phenyl) acetamide
In room temperature, to 4- ethyl -2- sulfydryl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -3,5- diformazan Nitrile (synthesis, 68mg, 0.226mmol are described in embodiment 69, step 1) and methanesulfonic acid 2- amino -2- oxo -1- (4- (three Methyl fluoride) phenyl) ethyl ester (49mg, 0.165mmol) is added in the suspension in n,N-Dimethylformamide (1.0mL) Et3N (0.063mL, 0.451mmol).Then the reaction mixture is stirred at room temperature overnight (20 hours).The reaction is mixed The filtrate is simultaneously purified (Gilson, 30mm x 50mm Gemini column, NH with reversed-phase HPLC by object filtering4OH modifying agent), it obtains 2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (4- (trifluoromethyl) phenyl) acetamide (44mg, 0.088mmol) is light yellow solid.LCMS m/z=503.5 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.08 (s, 1H), 7.76 (q, J=8.36Hz, 4H), 7.50 (s, 1H), 5.66 (s, 1H), 3.76-3.96 (m, 4H), 2.77 (q, J=7.60Hz, 2H), 2.61 (d, J=4.31Hz, 2H), 2.38-2.48 (m, 2H), 2.22 (s, 3H), 1.82-2.00 (m, 2H), 1.21 (t, J=7.60Hz, 3H).
Embodiment 234
2- ((6- (4- aminopiperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine, trifluoroacetate
Step 1:(4- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) piperazine -1- base) t-butyl carbamate
To chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in 3 step 2 of embodiment, 2.246g, TEA (4.16mL, 29.8mmol) 9.94mmol) is added in the solution in methylene chloride (30mL), then in 0 DEG C of addition piperazine Solution of the piperazine -1- carbamate (2g, 9.94mmol) in methylene chloride (30mL).The mixture is warmed to 25 DEG C and stir 16 hours.The mixture is poured into water (30mL).It separates each layer and organic phase is concentrated.By the residue column Chromatogram purification (uses dichloromethane eluent), obtains (4- (chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-) piperazine -1- base) ammonia Base t-butyl formate (2.5g, 6.40mmol, 64% yield), is brown solid.LCMS m/z=413.1 [M+Na]+。
Step 2:(4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) piperazine -1- base) t-butyl carbamate
To (4- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) piperazine -1- base) t-butyl carbamate (500mg, 1.279mmol) in the solution in n,N-Dimethylformamide (15mL) be added thioacetic acid potassium (219mg, 1.919mmol).The mixture is stirred 2 hours at 25 DEG C.Then methanesulfonic acid 2- amino -2- oxo -1- phenylethylester is added (synthesis, 275mg, 1.200mmol are described in embodiment 3, step 5) and the mixture is stirred 16 hours at 25 DEG C.It will The mixture is poured into water (20mL) and is extracted with ethyl acetate (20mL x 2).The organic phase is concentrated, which is used Column chromatography purifies (methylene chloride/methanol, 100:1), obtains (4- (6- ((2- amino -2- oxo -1- phenylethyl)-sulfenyl) - 3,5- dicyano -4- ethylpyridine -2- bases) piperazine -1- base) t-butyl carbamate (300mg) is light yellow solid. LCMS m/z=544.1 [M+Na]+。
Step 3:2- ((6- (4- aminopiperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide, trifluoroacetate
To addition (4- (6- ((2- amino -2- oxygen in the mixture of TFA (3mL, 38.9mmol) and methylene chloride (15mL) Generation -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperazine -1- base) t-butyl carbamate (300mg, 0.575mmol).The mixture is stirred 12 hours at 25 DEG C.The mixture is concentrated, then uses the residue Ethyl acetate (5mL) washing, obtains 2- ((6- (4- aminopiperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides, trifluoroacetate (110mg, 0.205mmol, 36% yield), is pale solid.LCMS m/z =422.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 9.45 (br s, 2H), 7.94 (s, 1H), 7.51-7.53 (m, 2H), 7.36-7.42 (m, 4H), 5.54 (s, 1H), 3.98 (br s, 4H), 3.01 (br s, 4H), 2.76-2.81 (m, 2H), 1.20-1.24 (m, 3H).
Embodiment 235:
2- ((6- ((2- amino -2- oxoethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides
By 2- ((chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-) sulfenyl) -2- phenyl-acetamides (in embodiment 52, Synthesis, 260mg, 0.73mmol are described in step 1) and thioacetic acid potassium (100mg, 0.87mmol) in DMF (30mL) Mixture stirs 0.5 hour at 20 DEG C.Then be added 2- chloroacetamide (273mg, 2.91mmol) and triethylamine (0.406mL, 2.91mmol), which is stirred at room temperature 13.5 hours.After reaction, by the reaction mixture be allocated in ethyl acetate and Between water.The organic phase is dried, filtered and is concentrated in vacuo with anhydrous sodium sulfate, the crude product is obtained, it is pure with column chromatography Change, obtains 2- ((6- ((2- amino -2- oxoethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide (133mg, 44% yield).LCMS m/z=412.0 [M+H]+。1H NMR (400MHz, DMSO-d6)δppm 7.80 (m, 2H), 7.70-7.35 (m, 7H), 5.84 (s, 1H), 4.22 (d, J=15.5Hz, 1H), 4.09 (d, J=15.4Hz, 1H), 2.83 (q, J=6.9Hz, 2H), 1.24 (t, J=6.9Hz, 3H).
Embodiment 236:
2- ((3,5- dicyano -4- ethyl -6- (pyrrolo- [3,4-c] pyrazoles -5 (1H, 4H, 6H)-yl) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides
The chloro- 4- ethyl -6- of step 1:2- (pyrrolo- [3,4-c] pyrazoles -5 (1H, 4H, 6H)-yl) pyridine -3,5- diformazan Nitrile
At 0 DEG C, to chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (in 3 step 2 of embodiment describe synthesis, 600mg, 2.65mmol) it is added Isosorbide-5-Nitrae in agitating solution in methylene chloride (20mL), 5,6- nafoxidines simultaneously [3,4-c] pyrazoles, Then triethylamine (1.108mL, 7.95mmol) is added in 2 hydrochlorides (531mg, 2.92mmol).By the reaction mixture in room temperature Stirring 5 hours.The reaction mixture is concentrated under reduced pressure, diluted with water (60mL) and is extracted with DCM (2x 80mL), will be closed And organic layer anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure.The residue is ground with ether (30mL), is filtered and dry It is dry, obtain the chloro- 4- ethyl -6- of 2- (pyrrolo- [3,4-c] pyrazoles -5 (1H, 4H, 6H)-yl) pyridine -3,5- dimethoxy nitrile (500mg, 62% yield), it is pale solid.LCMS m/z=299.1 [M+H]+。
Step 2:2- ((3,5- dicyano -4- ethyl -6- (pyrrolo- [3,4-c] pyrazoles -5 (1H, 4H, 6H)-yl) pyrrole Pyridine -2- base) sulfenyl) -2- phenyl-acetamides
In room temperature, to the chloro- 4- ethyl -6- of 2- (pyrrolo- [3,4-c] pyrazoles -5 (1H, 4H, 6H)-yl) pyridine -3,5- bis- Thioacetic acid potassium is added in the agitating solution in n,N-Dimethylformamide (20mL) in formonitrile HCN (500mg, 1.653mmol) (377mg, 3.31mmol) and the reaction mixture is stirred 2 hours.Then potassium carbonate (457mg, 3.31mmol) is added, then Be added methanesulfonic acid 2- amino -2- oxo -1- phenylethylester (describe synthesis in 3 step 5 of embodiment, 582mg, 2.479mmol).The reaction mixture is stirred at room temperature 16 hours.The reaction mixture is quenched with cold water (50mL) and is used in combination EtOAc (2x 100mL) extraction.By combined organic layer Na2SO4It dries, filters and is concentrated under reduced pressure.By the crude material column Chromatogram purification obtains the brown solid of 240mg using silica gel (100-200 mesh, eluted with DCM/MeOH).By the solid system Standby type-HPLC is further purified.Pure fraction is lyophilized, 2- ((3,5- dicyano -4- ethyl -6- (pyrrolo-es [3,4-c] are obtained Pyrazoles -5 (1H, 4H, 6H)-yl) pyridine -2- base) sulfenyl) -2- phenyl-acetamides (30mg) are pale solid.LCMS m/ Z=430.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm12.83 (br s, 1H), 7.99 (br s, 1H), 7.65 (br S, 1H), 7.60-7.49 (m, 2H), 7.47-7.14 (m, 4H), 5.71 (s, 1H), 5.14-4.72 (m, 4H), 2.87-2.72 (m, 2H), 1.30-1.16 (m, 3H).
Embodiment 237
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (5- methoxypyridine - 2- yl) acetamide
Step 1:2- hydroxyl -2- (5- methoxypyridine -2- base) acetamide
Three are added in the solution in methylene chloride (40mL) to 5- methoxypyridine -2- formaldehyde (1.0g, 7.29mmol) Methyl cyanide silane (1.095mL, 8.75mmol).The mixture is stirred at room temperature overnight.The mixture is concentrated, brown is obtained Oil, by it with dense H2SO4(5mL, 94mmol) is handled 4 hours, is then poured into ice the reaction mixture and is used NH4OH tune Save pH to 9.The reaction mixture is usedConcentration, with silica gel column purification (40g column, 0-10% MeOH/DCM), 2- hydroxyl -2- (5- methoxypyridine -2- base) acetamide (1.09g, 5.98mmol, 82% yield) is obtained, For beige solid.LCMS m/z=183.0 [M+H]+。
Step 2: methanesulfonic acid 2- amino -1- (5- methoxypyridine -2- base) -2- oxoethyl ester
To 2- hydroxyl -2- (5- methoxypyridine -2- base) acetamide (1.09g, 5.98mmol) and TEA (1.668mL, Methane sulfonyl chloride (0.559mL, 7.18mmol) 11.97mmol) is added in the pulp solution in THF (35mL), by the reaction Mixture is stirred at room temperature overnight.The reaction mixture is diluted with DCM and water, separates each layer.Water layer is extracted with DCM (4x) It takes.Combined organic matter is washed with brine, Na is used2SO4It is dry, concentration.The residue is ground with DCM, obtains methanesulfonic acid 2- Amino -1- (5- methoxypyridine -2- base) -2- oxoethyl ester (533mg, 2.048mmol, 34% yield), it is solid for yellow Body.LCMS m/z=261.0 [M+H]+。
Step 3:2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (5- methoxy Yl pyridines -2- base) acetamide
To chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in embodiment 3, step 2,100mg, Dimethylamine (2M is in THF, 0.243mL, 0.487mmol) 0.442mmol) is added dropwise in the solution in DMF (3mL) in DMF Then TEA (0.154mL, 1.106mmol) is added in solution in (1.5mL).After stirring 2 hours, by thioacetic acid potassium (65.7mg, 0.575mmol) is added in the reaction mixture, is stirred for 3 hours.Then by methanesulfonic acid 2- amino -1- (5- Methoxypyridine -2- base) -2- oxoethyl ester (127mg, 0.487mmol) adds in the reaction solution.By the reaction mixture It is stirred at room temperature overnight.The reaction mixture reversed-phase HPLC is purified into (20-50% acetonitrile/water, 0.1%NH4OH is in water), Obtain 2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (5- methoxypyridine -2- base) Acetamide (86mg, 0.217mmol, 49% yield), is pale solid.LCMS m/z=397.2 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 1.21 (t, J=7.5Hz, 3H), 2.76 (q, J=7.4Hz, 2H), 3.32 (s, 6H), 3.83 (s, 3H), 5.66 (s, 1H), 7.34 (s, 1H), 7.43 (dd, J=8.6,3.0Hz, 1H), 7.57 (d, J=8.6Hz, 1H), 7.82 (s, 1H), 8.24 (d, J=2.8Hz, 1H).
Embodiment 238
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (5- picoline -2- Base) acetamide
Step 1:2- hydroxyl -2- (5- picoline -2- base) acetamide
Trimethyl cyanogen is added in the solution in DCM (40mL) to 5- picoline -2- formaldehyde (1.00g, 8.26mmol) Silane (1.446mL, 11.56mmol).The mixture is stirred at room temperature overnight.The mixture is concentrated, brown oil is obtained, it will It handles 4 hours with the concentrated sulfuric acid (5mL, 94mmol), then by the reaction mixture down in ice and using NH4OH adjust pH to 9.The reaction mixture is concentrated with silica gel, with silica gel column purification (40g column), use 0-10%MeOH/ DCM obtains 2- hydroxyl -2- (5- picoline -2- base) acetamide (1.04g, 6.26mmol, 76% yield), is yellow wax Shape solid.LCMS m/z=167.0 [M+H]+。
Step 2: methanesulfonic acid 2- amino -1- (5- picoline -2- base) -2- oxoethyl ester
To 2- hydroxyl -2- (5- picoline -2- base) acetamide (1.04g, 6.26mmol) and TEA (1.745mL, Methane sulfonyl chloride (0.585mL, 7.51mmol) 12.52mmol) is added in the pulp solution in THF (25mL).By the reaction Mixture is stirred at room temperature 3 hours.The reaction mixture is diluted with DCM and used water and salt water washing, uses Na2SO4It is dry, it is dense Contracting, obtains methanesulfonic acid 2- amino -1- (5- picoline -2- base) -2- oxoethyl ester (1.49g, 6.10mmol, 97% yield), It is orange waxy solid.LCMS m/z=245.0 [M+H]+。
Step 3:2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (5- methyl Pyridine -2- base) acetamide
To chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in embodiment 3, step 2,100mg, Dimethylamine (2M is in THF, 0.243mL, 0.487mmol) 0.442mmol) is added dropwise in the solution in DMF (3mL) in DMF Solution and TEA (0.154mL, 1.106mmol) in (1.5mL).Stirring 2 hours after, then by thioacetic acid potassium (65.7mg, It 0.575mmol) adds in the reaction mixture, is stirred for 3 hours.Then by methanesulfonic acid 2- amino -1- (5- methyl pyrrole Pyridine -2- base) -2- oxoethyl ester (119mg, 0.487mmol) adds in the reaction solution.The reaction mixture is stirred at room temperature Overnight.Reaction mixture RP-HPLC is purified into (20-50% acetonitrile/water, 0.1%NH4OH is in water), obtain canescence It is used methanol trituration, obtains 2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl)-by solid 2- (5- picoline -2- base) acetamide (68mg, 0.179mmol, 40% yield), is pale solid.LCMS m/z= 381.2[M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 1.21 (t, J=7.5Hz, 3H), 2.29 (s, 3H), 2.76 (q, J =7.6Hz, 2H), 3.31 (s, 6H), 5.67 (s, 1H), 7.35 (s, 1H), 7.53 (d, J=7.9Hz, 1H), 7.64 (dd, J= 8.0,1.6Hz, 1H), 7.84 (s, 1H), 8.35-8.40 (m, 1H).
Embodiment 239
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (2- fluorine pyridin-4-yl) acetamide
Step 1:2- (2- fluorine pyridin-4-yl) -2- hydroxyl acetamide
Trimethyl is added in the solution in methylene chloride (30mL) to 2- fluorine Pyridine-4-Carboxaldehyde (1.0g, 7.99mmol) Cyanogen silane (1.200mL, 9.59mmol).The mixture is stirred at room temperature overnight.The mixture is concentrated, light brown is obtained Oil, by it with dense H2SO4(5mL, 94mmol) is handled 4 hours, is then poured into ice the reaction mixture and is used NH4OH tune Save pH to 9.The reaction mixture is concentrated with silica gel, with silica gel column purification (40g column), use 0-10% MeOH/DCM obtains 2- (2- fluorine pyridin-4-yl) -2- hydroxyl acetamide (829mg, 4.87mmol, 61% yield), is yellow Solid.LCMS m/z=171.0 [M+H]+。
Step 2: methanesulfonic acid 2- amino -1- (2- fluorine pyridin-4-yl) -2- oxoethyl ester
To 2- (2- fluorine pyridin-4-yl) -2- hydroxyl acetamide (829mg, 4.87mmol) and TEA (1.358mL, Methane sulfonyl chloride (0.456mL, 5.85mmol) 9.74mmol) is added in the pulp solution in THF (25mL), which is mixed Object is closed to be stirred at room temperature overnight.The reaction mixture is concentrated with silica gel and use silica gel column purification (40g Column), using 0-10%MeOH/DCM, obtain methanesulfonic acid 2- amino -1- (2- fluorine pyridin-4-yl) -2- oxoethyl ester (925mg, 3.73mmol, 76% yield), it is pale solid.LCMS m/z=249.0 [M+H]+。
Step 3:2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) -2- (2- fluorine pyridin-4-yl) acetamide
To chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in embodiment 3, step 2,100mg, 0.442mmol) the dropwise addition 1- methyl-1 in the solution in DMF (2.5mL), 4- Diazesuberane (0.062mL, 0.487mmol) the solution in DMF (1.5mL).Stirring after sixty minutes, by thioacetic acid potassium (65.7mg, 0.575mmol) and TEA (0.185mL, 1.327mmol) adds to the reaction mixture, is stirred for 3 hours.Then by methanesulfonic acid 2- amino -1- (2- fluorine pyridin-4-yl) -2- oxoethyl ester (121mg, 0.487mmol) adds in the reaction solution.By the reaction mixture It is stirred at room temperature overnight.By the reaction mixture with silica gel purification (12g column), use 10-20%MeOH/ DCM is as eluant, eluent.Obtained fractions are concentrated to and are used the second silica gel column purification (12g, 20%MeOH/DCM), obtain 2- ((3,5- Dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (2- fluorine pyridine -4- Base) acetamide (50mg, 0.110mmol, 25% yield) is white solid.LCMS m/z=454.3 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 1.21 (t, J=7.6Hz, 3H), 1.88 (br.s., 2H), 2.22 (s, 3H), 2.31-2.49 (m, 3H), 2.57-2.69 (m, 1H), 2.77 (q, J=7.6Hz, 2H), 3.71-3.96 (m, 4H), 5.66 (s, 1H), 7.30 (s, 1H), 7.50 (d, J=5.3Hz, 1H), 7.61 (s, 1H), 8.12 (s, 1H), 8.27 (d, J=5.1Hz, 1H).
Embodiment 240:
2- ((3,5- dicyano -4- ethyl -6- (4- hydroxyl -4- (hydroxymethyl) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides
The chloro- 4- ethyl -6- of step 1:2- (4- hydroxyl -4- (hydroxymethyl) piperidin-1-yl) pyridine -3,5- dimethoxy nitrile
By chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in 3 step 2 of embodiment, 1.13g, 5.00mmol), 4- (hydroxymethyl) piperidines -4- alcohol (0.656g, 5.00mmol) and triethylamine (2.090mL, 15.00mmol) are molten In methylene chloride (5mL).The mixture is stirred 12 hours.The mixture is diluted and is washed with brine with DCM.It will be organic Layer dries and concentrates, and then by the residue column purification, obtains the chloro- 4- ethyl -6- of 2- (4- hydroxyl -4- (hydroxymethyl) piperazine Pyridine -1- base) pyridine -3,5- dimethoxy nitrile (1.2g, 3.74mmol, 75% yield).LCMS m/z=321 [M+H]+。
Step 2:2- ((3,5- dicyano -4- ethyl -6- (4- hydroxyl -4- (hydroxymethyl) piperidin-1-yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides
By the chloro- 4- ethyl -6- of 2- (4- hydroxyl -4- (hydroxymethyl) piperidin-1-yl) pyridine -3,5- dimethoxy nitrile (640mg, 1.995mmol) and thioacetic acid potassium (456mg, 3.99mmol) is dissolved in n,N-Dimethylformamide (3mL).The mixture is existed It is stirred at room temperature 1 hour.Then potassium carbonate (551mg, 3.99mmol) and methanesulfonic acid 2- amino -2- oxo -1- phenylethyl is added Ester (describes synthesis, 915mg, 3.99mmol in 3 step 5 of embodiment).The mixture is stirred at room temperature 12 hours.It will consolidate Body is removed by filtration and the filtrate is concentrated and preparative-HPLC is used to purify, and obtains 2- ((3,5- dicyano -4- ethyl -6- (4- hydroxyl -4- (hydroxymethyl) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- phenyl-acetamides (110mg, 0.244mmol, 12% yield).LCMS m/z=452 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.93 (s, 1H), 7.52 (d, J= 7.3Hz, 2H), 7.38-7.33 (m, 4H), 5.54 (s, 1H), 4.69 (t, J=5.7Hz, 1H), 4.46 (s, 1H), 4.41-4.37 (m, 2H), 3.44 (t, J=13.2Hz, 2H), 3.24 (d, J=5.7Hz, 2H), 2.75 (q, J=7.6Hz, 2H), 1.67 (tt, J =12.9,6.5Hz, 2H), 1.53-1.49 (m, 2H), 1.21 (t, J=7.6Hz, 3H).
Embodiment 241
2- ((3,5- dicyano -4- ethyl -6- (2- oxo -3- oxa- -1,8- diaza spiro [4.5] decyl- 8- yl) pyrrole Pyridine -2- base) sulfenyl) -2- phenyl-acetamides
The chloro- 4- ethyl -6- of step 1:2- (2- oxo -3- oxa- -1,8- diaza spiro [4.5] decyl- 8- yl) pyridine -3, 5- dimethoxy nitrile
By chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in 3 step 2 of embodiment, 250mg, 1.106mmol), 3- oxa- -1,8- diaza spiro [4.5] decyl- 2- ketone (173mg, 1.106mmol) and triethylamine (112mg, 1.106mmol) add to methylene chloride (10mL).The mixture is stirred 3 hours at 25 DEG C, then will volatilize object vacuum evaporation. DCM (50mL) and water (20mL) are added in the residue.Separation organic layer is simultaneously washed with brine, and is dried and concentrated.This is residual Excess silica gel chromatography obtains the chloro- 4- ethyl -6- of 2- (2- oxo -3- oxa- -1,8- diaza spiro [4.5] decyl- 8- yl) Pyridine -3,5- dimethoxy nitrile (100mg, 0.289mmol, 26% yield).LCMS m/z=345.9 [M+H]+。
Step 2:2- ((3,5- dicyano -4- ethyl -6- (2- oxo -3- oxa- -1,8- diaza spiro [4.5] decyl- 8- Base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides
By the chloro- 4- ethyl -6- of 2- (2- oxo -3- oxa- -1,8- diaza spiro [4.5] decyl- 8- yl) pyridine -3,5- two Formonitrile HCN (120mg, 0.347mmol) and thioacetic acid potassium (79mg, 0.694mmol) add to n,N-Dimethylformamide (20mL). The mixture is stirred 2 hours.Then methanesulfonic acid 2- amino -2- oxo -1- phenylethylester (is retouched in 3 step 5 of embodiment State synthesis, 159mg, 0.694mmol) it is added and stirs the mixture 15 hours.The solvent in vacuo is evaporated.Then will DCM (20mL) and water (10mL) add in the residue and separate organic layer and is washed with brine, and are dried and concentrated.By the remnants Object is purified with preparative-HPLC, obtains 2- ((3,5- dicyano -4- ethyl -6- (2- oxo -3- oxa- -1,8- diaza spiro [4.5] decyl- 8- yl) pyridine -2- base) sulfenyl) -2- phenyl-acetamides (70mg, 0.147mmol, 42% yield).LCMS m/z= 477.1[M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.29 (s, 1H), 7.92 (s, 1H), 7.52 (d, J=7.3Hz, 2H), 7.41-7.33 (m, 4H), 5.53 (s, 1H), 4.14 (s, 2H), 4.04-4.00 (m, 2H), 3.91-3.79 (m, 2H), 2.77 (q, J=7.5Hz, 2H), 1.88-1.67 (m, 4H), 1.21 (t, J=7.6Hz, 3H).
Embodiment 242
2- ((6- (4- amino -4- (hydroxymethyl) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides, trifluoroacetate
Step 1:(1- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) -4- (hydroxymethyl) piperidin-4-yl) ammonia Base t-butyl formate
By chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in 3 step 2 of embodiment, 400mg, 1.769mmol), (4- (hydroxymethyl) piperidin-4-yl) t-butyl carbamate (408mg, 1.769mmol) and triethylamine (179mg, 1.769mmol) is added in methylene chloride (30mL).The mixture is stirred 5 hours at 25 DEG C.Then DCM is added (50mL) and water (30mL).Separation organic layer is simultaneously washed with brine, and is dried and concentrated.By the residue silica gel chromatography, Obtain (1- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) -4- (hydroxymethyl) piperidin-4-yl) t-butyl carbamate (350mg, 0.834mmol, 47% yield).LCMS m/z=442.1 [M+Na]+。
Step 2:(1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) -4- (hydroxymethyl) piperidin-4-yl) t-butyl carbamate
By (1- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) -4- (hydroxymethyl) piperidin-4-yl) amino first Tert-butyl acrylate (300mg, 0.714mmol) and thioacetic acid potassium (163mg, 1.429mmol) add to n,N-Dimethylformamide (20mL).By the mixture 25 DEG C stir 2 hours, then be added methanesulfonic acid 2- amino -2- oxo -1- phenylethylester ( Synthesis, 328mg, 1.429mmol are described in 3 step 5 of embodiment).The mixture is stirred 15 hours.The solvent in vacuo is steamed Hair.Then DCM (50mL) and water (20mL) are added in the residue.Separation organic layer is simultaneously washed with brine, and is dried and concentrated. By the residue silica gel chromatography, (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyan is obtained Base -4- ethylpyridine -2- base) -4- (hydroxymethyl) piperidin-4-yl) t-butyl carbamate (150mg, 0.272mmol, 38% Yield).LCMS m/z=550.9 [M+H]+。
Step 3:2- ((6- (4- amino -4- (hydroxymethyl) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides, trifluoroacetate
At 0 DEG C, by (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) -4- (hydroxymethyl) piperidin-4-yl) t-butyl carbamate (150mg, 0.272mmol) adds to methylene chloride (20mL) and 2,2,2- trifluoroacetic acids (31.1mg, 0.272mmol) are added in the solution in 5mL methylene chloride.This is mixed It closes object to be stirred overnight, then removes the solvent.Residue preparative-HPLC is purified, 2- ((6- (4- amino-is obtained 4- (hydroxymethyl) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides, trifluoroacetic acid Salt (38mg, 0.067mmol, 25% yield).LCMS m/z=451.1 [M+H]+。1H NMR (400MHz, DMSO-d6)δppm 8.06 (bs, 3H), 7.98 (s, 1H), 7.52 (d, J=7.2Hz, 2H), 7.41-7.34 (m, 4H), 5.60 (bs, 1H), 5.54 (s, 1H), 4.21-3.99 (m, 2H), 3.92-3.68 (m, 2H), 3.62 (s, 2H), 2.78 (q, J=7.5Hz, 2H), 1.92- 1.89 (m, 2H), 1.86-1.59 (m, 2H), 1.22 (t, J=7.6Hz, 3H).
Embodiment 243
2- ((6- (4- (amino methyl) -4- hydroxy piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides, trifluoroacetate
Step 1:((1- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) -4- hydroxy piperidine -4- base) methyl) ammonia Base t-butyl formate
To chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in 3 step 2 of embodiment, 1g, ((4- hydroxy piperidine -4- base) methyl) t-butyl carbamate 4.42mmol) is added in the solution in methylene chloride (50mL) (1.019g, 4.42mmol) and triethylamine (0.448g, 4.42mmol).The reaction mixture is stirred 15 hours at 25 DEG C.It will The solvent removes and water (50mL) and DCM (50mL) is added to the residue.By organic phase Na2SO4It dries and concentrates.It will The residue obtains product ((1- (chloro- 3, the 5- dicyano -4- ethylpyridine-of 6- with silica gel chromatography (PE/EA=1:2) 2- yl) -4- hydroxy piperidine -4- base) methyl) t-butyl carbamate (1.1g, 2.62mmol, 59% yield).LCMS m/z= 441.8[M+Na]+。
Step 2:((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) -4- hydroxy piperidine -4- base) methyl) t-butyl carbamate
To ((1- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) -4- hydroxy piperidine -4- base) methyl) amino first Tert-butyl acrylate (2g, 4.76mmol) be added in the solution in n,N-Dimethylformamide (80mL) thioacetic acid potassium (1.088g, 9.53mmol).By the mixture in 25 DEG C of stirring 2h, be then added methanesulfonic acid 2- amino -2- oxo -1- phenylethylester ( Synthesis, 2.184g, 9.53mmol are described in 3 step 5 of embodiment).The mixture is stirred 15 hours at 25 DEG C.By the solvent It removes and adds to water (50mL) and DCM (50mL) in the residue.By organic phase Na2SO4It dries and concentrates.This is residual Excess obtains ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl)-with silica gel chromatography (PE/EA=5:1) 3,5- dicyano -4- ethylpyridine -2- bases) -4- hydroxy piperidine -4- base) methyl) t-butyl carbamate (2g, 3.63mmol, 76% yield), it is faint yellow solid.LCMS m/z=550.8 [M+H]+。
Step 6:2- ((6- (4- (amino methyl) -4- hydroxy piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides, trifluoroacetate
To ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) -4- hydroxy piperidine -4- base) methyl) solution of the t-butyl carbamate (1g, 1.816mmol) in methylene chloride (30mL) 2,2,2- trifluoroacetic acids (0.621g, 5.45mmol) of middle addition.The mixture is stirred 15 hours at 25 DEG C.The solvent under reduced pressure removes It goes, obtains 2- ((6- (4- (amino methyl) -4- hydroxy piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides trifluoroacetate (200mg, 0.444mmol, 24% yield), is solid.LCMS m/z=450.9 [M+ H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.94 (s, 1H), 7.86 (br s, 3H), 7.52 (d, J=7.2Hz, 2H), 7.39-7.33 (m, 4H), 5.55 (s, 1H), 4.41-4.29 (m, 2H), 3.52 (t, 2H), 2.93-2.71 (m, 4H), 1.69- 1.63 (m, 4H), 1.21 (t, 3H).
Embodiment 244:
2- (3- benzoylphenyl) -2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxyethyl) -1,4- phenodiazine Trioxepane -1- base) pyridine -2- base) sulfenyl) acetamide
Step 1:(3- (bromomethyl) phenyl) (phenyl) ketone
By phenyl (m- tolyl) ketone (2.0g, 10mmol), 1- bromine pyrrolidines -2,5- diketone (2.0g, 11mmol) (E) -2,2'- (diazene -1,2- diyl) bis- (2- methyl propionitrile) (0.167g, 1.02mmol) is in CCl4It is molten in (60mL) Liquid is refluxed overnight.After being cooled to room temperature, which is washed with water (3x 20mL), dry and vacuum concentration.This is residual Excess is applied on silicagel column and with ethyl acetate/hexane, and 1:20 elution obtains (3- (bromomethyl) phenyl) (phenyl) ketone (1.85g, 6.73mmol, 66% yield), is white solid.LCMS m/z=274.8 [M+H]+。
Step 2:2- (3- benzoylphenyl) acetonitrile
To (3- (bromomethyl) phenyl) (phenyl) ketone (2.74g, 9.96mmol) in the solution in acetonitrile (40.0mL) It is added potassium carbonate (3.44g, 24.9mmol).At 0 DEG C, it is mixed that trimethylsilyl cyanide (3.95g, 39.8mmol) is added dropwise to the reaction Close object.Then the mixture is stirred overnight at 80 DEG C.The reaction mixture is cooled to room temperature.By acquired solution 50mL water Then dilution is extracted with 3x 40mL ethyl acetate.Organic layer is merged, with sodium carbonate (aqueous solution) and salt water washing, it is dry and Vacuum concentration.The residue is applied to silicagel column and with ethyl acetate/hexane, 1:5 elution obtains 2- (3- Benzoylbenzene Base) acetonitrile (800mg, 3.62mmol, 36% yield).LCMS m/z=222.1 [M+H]+。
Step 3:2- (3- benzoylphenyl) -2- bromoacetonitrile
To 2- (3- benzoylphenyl) acetonitrile (800mg, 3.62mmol) in carbon tetrachloride (30
ML 1- bromine pyrrolidines -2,5- diketone (772mg, 4.34mmol) is added in the solution in), (E) -2 then is added, 2'- (diazene -1,2- diyl) bis- (2- methyl propionitrile) (297mg, 1.81mmol).Then the mixture is flowed back 2 days.It is cooling To room temperature, which is washed with water.Organic layer is washed with water, MgSO is used4It dries and is evaporated to dryness.By the crude material Material is applied to silicagel column, obtains 2- (3- benzoylphenyl) -2- bromoacetonitrile (440mg, 1.47mmol, 41% yield), is Yellow solid.LCMS m/z=300.0 [M+H]+。
Step 4:2- (3- benzoylphenyl) -2- acetbromamide
To 2- (3- benzoylphenyl) -2- bromoacetonitrile (440mg, 1.47mmol) in tetrahydrofuran (18mL) and water Palladium chloride (II) (26mg, 0.15mmol) is added in solution in (6mL), acetamide (260mg, 4.40mmol) then is added. Then the mixture is stirred at room temperature 2 hours.Acquired solution 3x 20mL ethyl acetate is extracted.Organic layer is merged, is used Aqueous sodium carbonate and salt water washing, dry and vacuum concentration.By the residue be applied to silicagel column and with ethyl acetate/oneself Alkane, 1:2 elution, obtains 2- (3- benzoylphenyl) -2- acetbromamide (352mg, 1.11mmol, 75% yield), for Huang Color oil.LCMS m/z=318.0 [M+H]+。
Step 5:4- (2- hydroxyethyl) -1,4- Diazesuberane -1- t-butyl formate
To Isosorbide-5-Nitrae-solution of the Diazesuberane base -1- t-butyl formate (1.0g, 4.99mmol) in toluene (30mL) Middle addition ethylene bromohyrin (0.936g, 7.49mmol).The mixture is stirred overnight at 80 DEG C.The solvent is removed under reduced pressure It goes.Ethyl acetate (30mL) is added and the mixture is stirred at room temperature 2 hours.Solid by filtration is collected.By gained Mixture is washed with 2x 30mL ethyl acetate, obtains 4- (2- hydroxyethyl)-Isosorbide-5-Nitrae-Diazesuberane -1- t-butyl formate (900mg, 3.68mmol) is white solid.LCMS m/z=245.0 [M+H]+。
The chloro- 4- ethyl -6- of step 6:2- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base) pyridine -3,5- Dimethoxy nitrile
To 4- (2- hydroxyethyl)-Isosorbide-5-Nitrae-Diazesuberane -1- t-butyl formate (400mg, 1.64mmol) in DCM Trifluoroacetic acid (6.0mL) is added in solution in (6.0mL).The reaction mixture is stirred at room temperature overnight.By the solvent and Trifluoroacetic acid is removed under reduced pressure, and obtains yellow oil.To chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (in embodiment 3, step 2 In describe synthesis, 376mg, 1.66mmol) and triethylamine (337mg, 3.33mmol) in the solution in acetonitrile (20mL) plus Enter above-mentioned yellow oil.Then the mixture is stirred at room temperature overnight.The reaction is gone out by the way that 60mL water quenching is added.Gained is molten Liquid is extracted with 3x 40mL ethyl acetate.Organic layer is merged, with aqueous sodium carbonate and salt water washing, drying and vacuum concentration, Obtain the chloro- 4- ethyl -6- of 2- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base) pyridine -3,5- dimethoxy nitrile (400mg, 1.20mmol) is yellow solid.LCMS m/z=334.1 [M+H]+。
Step 7:2- (3- benzoylphenyl) -2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxyethyl) -1, 4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) acetamide
To the chloro- 4- ethyl -6- of 2- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base) pyridine -3,5- diformazan Nitrile (200mg, 0.60mmol) be added in the solution in n,N-Dimethylformamide (20mL) thioacetic acid potassium (75mg, 0.66mmol).The reaction mixture is stirred at room temperature 30 minutes, then by 2- (3- benzoylphenyl) -2- acetbromamide (191mg, 0.599mmol) and triethylamine (152mg, 1.50mmol) add in the reaction.The reaction mixture is stirred in room temperature It mixes overnight.The mixture is poured into 20mL water.Gained mixture 3x 20mL ethyl acetate is extracted.Organic layer is merged, With sodium carbonate (aqueous solution) and salt water washing, drying is simultaneously concentrated in vacuo, obtains raw product, be yellow oil.By the remnants Object is purified with preparative-HPLC, obtains 2- (3- benzoylphenyl) -2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxyls Ethyl)-Isosorbide-5-Nitrae-Diazesuberane -1- base) pyridine -2- base) sulfenyl) acetamide (40mg, 0.07mmol), it is solid for yellow Body.LCMS m/z=568.9 [M+H]+。1H NMR (400MHz, MeOD) δ ppm 7.98 (s, 1H), 7.84 (s, 1H), 7.78 (t, J=8.1Hz, 3H), 7.68 (s, 1H), 7.58 (dt, J=15.4,7.7Hz, 3H), 5.66 (s, 1H), 4.01 (dd, J=15.9, 10.1Hz, 4H), 3.71 (t, J=5.7Hz, 2H), 3.06 (s, 2H), 2.97-2.85 (m, 4H), 2.80 (s, 2H), 2.11 (s, 2H), 1.32 (t, J=7.6Hz, 3H).
Embodiment 245:
2- (4- benzoylphenyl) -2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxyethyl) -1,4- phenodiazine Trioxepane -1- base) pyridine -2- base) sulfenyl) acetamide
Step 1:(4- (bromomethyl) phenyl) (phenyl) ketone
By phenyl (p- tolyl) ketone (5.0g, 25.5mmol), 1- bromine pyrrolidines -2,5- diketone (4.99g, 28.0mmol) and (E) -2,2'- (diazene -1,2- diyl) bis- (2- methyl propionitrile) (0.209g, 1.27mmol) is in CCl4 Solution at reflux overnight in (80.0mL).After being cooled to room temperature, which is washed with water (3x 50mL), it is dry and Vacuum concentration.The residue is applied to silicagel column and with ethyl acetate/hexane, 1:20 elution obtains (4- (bromomethyl) benzene Base) (phenyl) ketone (4.5g, 16mmol, 64% yield) is white solid.LCMS m/z=275.0 [M+H]+。
Step 2:2- (4- benzoylphenyl) acetonitrile
To (4- (bromomethyl) phenyl) (phenyl) ketone (2.74g, 9.96mmol) in the solution in acetonitrile (40.0ml) It is added potassium carbonate (3.44g, 24.9mmol).At 0 DEG C, it is mixed that trimethylsilyl cyanide (3.95g, 39.8mmol) is added dropwise to the reaction Close object.The mixture is stirred overnight at 80 DEG C.The reaction mixture is cooled to room temperature.Acquired solution 50mL water is diluted And it is extracted with ethyl acetate (3x 40mL).Organic layer is merged, with aqueous sodium carbonate and salt water washing, dry and vacuum is dense Contracting.The residue is applied to silicagel column and is eluted with ethyl acetate/hexane (1:5), 2- (4- benzoylphenyl) second is obtained Nitrile (820mg, 3.71mmol, 37% yield).LCMS m/z=222.1 [M+H]+。
Step 3:2- (4- benzoylphenyl) -2- bromoacetonitrile
Add in the solution in carbon tetrachloride (30mL) to 2- (4- benzoylphenyl) acetonitrile (820mg, 3.71mmol) Enter N- bromine succinimide (792mg, 4.45mmol) and AIBN (304mg, 1.85mmol).The mixture is flowed back 2 days.It is cooling To room temperature, which is washed with water.Organic layer is washed with water, dry (MgSO4) and be evaporated to dryness.By the residue With silica gel column purification, 2- (4- benzoylphenyl) -2- bromoacetonitrile (380mg, 1.27mmol, 34% yield) is obtained, for Huang Color solid.LCMS m/z=300.0 [M+H]+。
Step 4:2- (4- benzoylphenyl) -2- acetbromamide
By 2- (4- benzoylphenyl) -2- bromoacetonitrile (380mg, 1.27mmol) in tetrahydrofuran (18mL) and water Palladium chloride (II) (22mg, 0.13mmol) is added in solution in (6mL), acetamide (224mg, 3.80mmol) then is added. The mixture is stirred at room temperature 2 hours.Acquired solution is extracted with ethyl acetate (3x 20mL).Organic layer is merged, carbon is used Acid sodium aqueous solution and salt water washing, drying are simultaneously concentrated in vacuo.The residue is applied to silicagel column and uses ethyl acetate/hexane (1:2) elution, obtains 2- (4- benzoylphenyl) -2- acetbromamide (300mg, 0.94mmol, 74% yield), is yellow Oil.LCMS m/z=318.0 [M+H]+。
Step 5:2- (4- benzoylphenyl) -2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxyethyl) -1, 4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) acetamide
To the chloro- 4- ethyl -6- of 2- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base) pyridine -3,5- diformazan Nitrile (synthesis, 200mg, 0.60mmol are described in embodiment 244, step 6) is in n,N-Dimethylformamide (20mL) Thioacetic acid potassium (75mg, 0.66mmol) is added in solution.The reaction mixture is stirred at room temperature 30 minutes.Then by 2- (4- benzoylphenyl) -2- acetbromamide (191mg, 0.60mmol) and triethylamine (152mg, 1.50mmol) add to the reaction The mixture is simultaneously stirred at room temperature overnight by mixture.The mixture is poured into 20mL water.By gained mixture acetic acid second Ester (3x 20mL) extraction.Organic layer is merged, with aqueous sodium carbonate and salt water washing, dry and vacuum concentration is obtained crude Product is yellow oil.Residue preparative-HPLC is purified, 2- (4- benzoylphenyl) -2- ((3,5- bis- is obtained Cyano -4- ethyl -6- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) acetamide (70mg, 0.12mmol, 20% yield), is yellow solid.LCMS m/z=568.9 [M+H]+。1H NMR (400MHz, MeOD) δ ppm 7.83 (m, J=15.5,7.8Hz, 4H), 7.76-7.66 (m, 3H), 7.57 (t, J=7.7Hz, 2H), 5.60 (s, 1H), 4.09 (bs, 4H), 3.94-3.90 (m, 2H), 3.60 (bs, 6H), 2.97 (q, J=7.5Hz, 2H), 2.41 (bs, 2H), 1.34 (t, J=7.6Hz, 3H).
Embodiment 246
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (2- picoline -4- base) acetamide
Step 1:2- hydroxyl -2- (2- picoline -4- base) acetamide
Front three is added in the solution in methylene chloride (25mL) to 2- picoline -4- formaldehyde (1.0g, 8.26mmol) Base cyanogen silane (1.239mL, 9.91mmol).The mixture is stirred at room temperature overnight.The mixture is concentrated, light brown is obtained Oil, by it with dense H2SO4(5mL, 94mmol) is handled 4 hours, is then poured into ice the reaction mixture and is used NH4OH tune Save pH to 9.The mixture is concentrated with silica gel, with silica gel column purification (40g column), use 0-10% MeOH/DCM obtains 2- hydroxyl -2- (2- picoline -4- base) acetamide (487mg, 2.93mmol, 36% yield), for Huang Color solid.LCMS m/z=167.0 [M+H]+。
Step 2: methanesulfonic acid 2- amino -1- (2- picoline -4- base) -2- oxoethyl ester
To 2- hydroxyl -2- (2- picoline -4- base) acetamide (487mg, 2.93mmol) and TEA (0.817mL, Methane sulfonyl chloride (0.274mL, 3.52mmol) 5.86mmol) is added in the pulp solution in THF (20mL).The reaction is mixed Object is closed to be stirred at room temperature overnight.The reaction mixture is concentrated with silica gel and use silica gel column purification (40g Column uses 0-10%MeOH/DCM), obtain methanesulfonic acid 2- amino -1- (2- picoline -4- base) -2- oxoethyl ester (520mg, 2.129mmol, 73% yield), is pale solid.LCMS m/z=245.0 [M+H]+。
Step 3:2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) -2- (2- picoline -4- base) acetamide
By 4- ethyl -2- sulfydryl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -3,5- dimethoxy nitrile (in reality Apply example 69, synthesis, 99mg, 0.328mmol described in step 1), methanesulfonic acid 2- amino -1- (2- picoline -4- base) -2- The reaction mixture of oxoethyl ester (80mg, 0.328mmol) and TEA (0.091mL, 0.655mmol) in DMF (4mL) exists It is stirred overnight at room temperature.By the reaction mixture with silica gel purification (24g column), use 15-20%MeOH/ DCM is as eluant, eluent.Obtained fractions are concentrated and are used the second silica gel column purification (12g column), using 20%MeOH/DCM, obtain 2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (2- methyl Pyridin-4-yl) acetamide (60mg, 0.133mmol, 41% yield) is pale solid.LCMS m/z=450.2 [M+H ]+。1H NMR (400MHz, DMSO-d6) δ ppm 1.21 (t, J=7.6Hz, 3H), 1.92 (br.s., 2H), 2.21-2.33 (m, 3H), 2.47 (s, 3H), 2.71-2.61 (m, 4H), 2.77 (q, J=7.5Hz, 2H), 3.75-4.01 (m, 4H), 5.52 (s, 1H), 7.28-7.33 (m, 1H), 7.37 (s, 1H), 7.50 (s, 1H), 8.05 (s, 1H), 8.44 (d, J=5.1Hz, 1H).
Embodiment 247
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (3- (pyrrolidin-1-yl) phenyl) acetamide
Step 1:2- hydroxyl -2- (3- (pyrrolidin-1-yl) phenyl) acetamide
At 20 DEG C, to 3- (pyrrolidin-1-yl) benzaldehyde (351mg, 2.003mmol) in methylene chloride (10mL) Trimethylsilyl cyanide (0.349mL, 2.60mmol) is added in solution.Then by the reaction mixture mutually synthermal stirred Night.After 20 DEG C are stirred overnight, the required product that LCMS instruction generates is few.By the zinc iodide of catalytic amount (32.0mg, It 0.100mmol) adds in the reaction mixture.Then the reaction mixture is warmed to 40 DEG C, is stirred for 24 mutually synthermal Hour.Then the mixture is concentrated by rotary evaporation.Then by gained brown oil with the concentrated sulfuric acid (1.1mL, 20.64mmol) It handles and the mixture is stirred at room temperature 4 hours, LCMS instruction at this time is remained without intermediate and there are required products.Then will The reaction mixture pours into ice and uses NH4PH is adjusted to~9 by OH.Then the mixture is concentrated, obtains the crude product.It will Raw product reversed-phase HPLC purifies (Gilson, 30mm Gemini column, NH4OH modifying agent), obtain 2- hydroxyl -2- (3- (pyrrole Cough up alkane -1- base) phenyl) acetamide (81mg) LCMS m/z=221.1 [M+H]+。
Step 2: methanesulfonic acid 2- amino -2- oxo -1- (3- (pyrrolidin-1-yl) phenyl) ethyl ester
At 0 DEG C, to 2- hydroxyl -2- (3- (pyrrolidin-1-yl) phenyl) acetamide (79mg, 0.359mmol), DIEA Methane sulphur is added in (0.078mL, 0.448mmol) and DMAP (4mg, 0.033mmol) in the solution in methylene chloride (2.0mL) Acyl chlorides (0.035mL, 0.448mmol).Then the reaction mixture is warmed to 20 DEG C and is stirred overnight mutually synthermal.It should Reaction mixture dilutes with DCM and uses 1N HCl (2x), saturated brine (1x), then water washing.Then organic layer is dry (MgSO4) and concentration, methanesulfonic acid 2- amino -2- oxo -1- (3- (pyrrolidin-1-yl) phenyl) ethyl ester (39mg) is obtained, For brown oil.LCMS m/z=299.1 [M+H]+。
Step 3:2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) -2- (3- (pyrrolidin-1-yl) phenyl) acetamide
In room temperature, to 4- ethyl -2- sulfydryl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -3,5- diformazan Nitrile (synthesis, 68mg, 0.226mmol are described in embodiment 69, step 1) and methanesulfonic acid 2- amino -2- oxo -1- (4- (three Methyl fluoride) phenyl) ethyl ester (49mg, 0.165mmol) is added in the suspension in n,N-Dimethylformamide (1.0mL) Et3N (0.063mL, 0.451mmol).Then the reaction mixture is stirred at room temperature.It is after being stirred at room temperature overnight, this is thick Substance reversed-phase HPLC purifies (Gilson, 30mm x 50mm Gemini column, NH4OH modifying agent), obtain 2- ((3,5- dicyan Base -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (3- (pyrrolidin-1-yl) Phenyl) acetamide (7mg).LCMS m/z=504.3 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.81 (s, 1H), 7.28 (s, 1H), 7.14 (t, J=7.86Hz, 1H), 6.69 (d, J=8.11Hz, 1H), 6.63-6.66 (m, 1H), 6.48 (dd, J=1.77,8.36Hz, 1H), 5.38 (s, 1H), 3.95 (t, J=4.31Hz, 2H), 3.90 (t, J=6.08Hz, 2H), 3.15- 3.24 (m, 4H), 2.77 (q, J=7.60Hz, 2H), 2.64-2.70 (m, 2H), 2.26 (s, 3H), 1.91-1.98 (m, 6H), 1.21 (t, J=7.60Hz, 3H).Two protons is not measured.
Embodiment 248
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (3- fluorine pyridin-4-yl) acetamide
Step 1:2- (3- fluorine pyridin-4-yl) -2- hydroxyl acetamide
Trimethyl is added in the solution in methylene chloride (25mL) to 3- fluorine Pyridine-4-Carboxaldehyde (1.0g, 7.99mmol) Cyanogen silane (1.200mL, 9.59mmol).The mixture is stirred at room temperature overnight.The mixture is concentrated, light brown is obtained Oil, by it with dense H2SO4(5mL, 94mmol) is handled 4 hours, is then poured into ice the reaction mixture and is used NH4OH tune Save pH to 9.The solid is filtered, obtaining 2- (3- fluorine pyridin-4-yl) -2- hydroxyl acetamide, (748mg, 4.40mmol, 55% are produced Rate), it is pale solid.LCMS m/z=171.0 [M+H]+。
Step 2: methanesulfonic acid 2- amino -1- (3- fluorine pyridin-4-yl) -2- oxoethyl ester
To 2- (3- fluorine pyridin-4-yl) -2- hydroxyl acetamide (745mg, 4.38mmol) and TEA (1.221mL, Methane sulfonyl chloride (0.409mL, 5.25mmol) 8.76mmol) is added in the pulp solution in THF (20mL).The reaction is mixed Object is closed to be stirred at room temperature overnight.The reaction mixture is concentrated with silica gel and use silica gel column purification (40g Column, 0-10%MeOH/DCM), obtain methanesulfonic acid 2- amino -1- (3- fluorine pyridin-4-yl) -2- oxoethyl ester (970mg, 3.91mmol, 89% yield), it is beige solid.LCMS m/z=249.1 [M+H]+。
Step 3:2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) -2- (3- fluorine pyridin-4-yl) acetamide
By 4- ethyl -2- sulfydryl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -3,5- dimethoxy nitrile (in reality Apply example 69, synthesis, 109mg, 0.363mmol described in step 1), methanesulfonic acid 2- amino -1- (3- fluorine pyridin-4-yl) -2- oxygen For ethyl ester (75mg, 0.302mmol) and TEA (0.084mL, 0.604mmol) in the reaction mixture in DMF (3mL) It is stirred overnight at room temperature.By the reaction mixture with silica gel purification (12g column, uses 10-20%MeOH/DCM As eluant, eluent).Obtained fractions are concentrated and are used the second silica gel column purification (12g column, 20%MeOH/DCM), 2- ((3,5- is obtained Dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (3- fluorine pyridine -4- Base) acetamide (79mg, 0.174mmol, 58% yield) is pale solid.LCMS m/z=454.3 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 1.22 (t, J=7.6Hz, 3H), 1.91 (br.s., 2H), 2.23-2.31 (m, 3H), 2.34- 2.49 (m, 2H), 2.55-2.73 (m, 2H), 2.79 (q, J=7.6Hz, 2H), 3.68-3.98 (m, 4H), 5.84 (s, 1H), 7.57 (dd, J=6.3,5.1Hz, 1H), 7.65 (s, 1H), 8.07 (s, 1H), 8.46 (d, J=4.8Hz, 1H), 8.63 (d, J= 1.5Hz, 1H).
Embodiment 249
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (2,5- difluoro pyridine -4- base) acetamide
Step 1:2- (2,5- difluoro pyridine -4- base) -2- hydroxyl acetamide
It is added in the solution in methylene chloride (50mL) to 2,5- Difluoro-pyridin -4- formaldehyde (1.9g, 13.28mmol) Trimethylsilyl cyanide (1.993mL, 15.93mmol).The mixture is stirred at room temperature overnight.The mixture is concentrated, is obtained Brown oil, by it with dense H2SO4(7mL, 131mmol) is handled 4 hours, and then the reaction mixture is poured into ice and used NH4OH adjusts pH to 9.The reaction mixture is usedConcentration, with silica gel column purification (40g column, Use 0-15%MeOH/DCM), obtain 2- (2,5- difluoro pyridine -4- base) -2- hydroxyl acetamide (1.41g, 7.49mmol, 56% yield), it is yellow solid.LCMS m/z=189.0 [M+H]+。
Step 2: methanesulfonic acid 2- amino -1- (2,5- difluoro pyridine -4- base) -2- oxoethyl ester
To 2- (2,5- difluoro pyridine -4- base) -2- hydroxyl acetamide (1.41g, 7.49mmol) and TEA (2.089mL, Methane sulfonyl chloride (0.701mL, 8.99mmol) 14.99mmol) is added in the pulp solution in THF (40mL).By the reaction Mixture is stirred at room temperature overnight.The reaction mixture is diluted with DCM and water, separates each layer.Water layer is extracted with DCM (2x) It takes.Combined organic matter is washed with brine, Na is used2SO4Dry, concentration obtains methanesulfonic acid 2- amino -1- (2,5- difluoro pyrroles Pyridine -4- base) -2- oxoethyl ester (1.88g, 7.06mmol, 94% yield) is yellow solid.LCMS m/z=267.0 [M +H]+。
Step 3:2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) -2- (2,5- difluoro pyridine -4- base) acetamide
By 4- ethyl -2- sulfydryl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -3,5- dimethoxy nitrile (in reality Apply example 69, synthesis, 109mg, 0.361mmol described in step 1), methanesulfonic acid 2- amino -1- (2,5- difluoro pyridine -4- base) - The reaction mixture of 2- oxoethyl ester (80mg, 0.301mmol) and TEA (0.084mL, 0.601mmol) in DMF (3mL) It is stirred at room temperature overnight.By the reaction mixture with silica gel purification (12g column, uses 10-20%MeOH/ DCM is as eluant, eluent).Obtained fractions are concentrated and are used the second silica gel column purification (12g uses 20%MeOH/DCM), 2- is obtained ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (2,5- bis- Fluorine pyridin-4-yl) acetamide (44mg, 0.093mmol, 31% yield) is pale solid.LCMS m/z=472.3 [M+ H]+。1H NMR (400MHz, pyridine-d5) δ ppm 9.33 (s, 1H), 9.21 (s, 1H), 8.29 (s, 1H), 7.75 (dd, J= 4.6,2.8Hz, 1H), 6.28 (s, 1H), 4.15 (t, J=4.4Hz, 2H), 3.82-3.93 (m, 2H), 3.00-3.18 (m, 2H), 2.72-2.86 (m, 4H), 2.43 (s, 3H), 2.17 (br.s., 2H), 1.15 (t, J=7.6Hz, 3H).
Embodiment 250:
2- ((3,5- dicyano -6- (4- (2,5- dioxoimidazolidin -1- base) piperidin-1-yl) -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides
Step 1:3- (1- benzyl piepridine -4- base) imidazoline -2,4- diketone
By 1- benzyl piepridine -4- amine (5g, 26.3mmol) in CHCl3Solution in (30mL) is added dropwise to 2- isocyanic acid acetic acid Ethyl ester (2.5g, 19.36mmol) is in CHCl3It is stirred 15 minutes in agitating solution in (70mL) and by the reaction mixture.So Afterwards by reaction mixture evaporation and drying, yellow solid is obtained.The yellow solid is dissolved in EtOH (15mL) and HCl (10M, water Solution, 15mL) solution and be heated to reflux 3 hours.After 3 hours, which is evaporated and by the solution NaOH solution (5N, 30mL) is neutralized, and then uses NaHCO3(30mL) saturated solution neutralizes.The mixture is extracted and incited somebody to action with DCM (2x 50mL) Combined organic layer anhydrous Na2SO4It dries, filters and is concentrated.By crude compound silica gel chromatography (100-200 Mesh uses the petroleum ether solution of 0-70%EtOAc as eluant, eluent).By pure fraction collector, concentration and drying obtain 3- (1- Benzyl piepridine -4- base) imidazoline -2,4- diketone (3g, 55% yield) is yellow solid.LCMS m/z=274.2 [M+H ]+。
Step 2:3- (piperidin-4-yl) imidazoline -2,4- diketone
In room temperature, 10%Pd/C (600mg, 0.564mmol) is added into 3- (1- benzyl piepridine -4- base) imidazoline -2,4- Solution of the diketone (2.7g, 9.60mmol) in MeOH (200mL) simultaneously stirs the reaction mixture under a hydrogen atmosphere (balloon) 16 hours.The reaction mixture is passed throughPad filtering, is washed with MeOH (300mL).The filtrate is concentrated and is dried, 3- (piperidin-4-yl) imidazoline -2,4- diketone (1g) is obtained, is gray solid.LCMS m/z=184.2 [M+H]+。
The chloro- 6- of step 3:2- (4- (2,5- dioxoimidazolidin -1- base) piperidin-1-yl) -4- ethylpyridine -3,5- two Formonitrile HCN
At 0 DEG C, 3- (piperidin-4-yl) imidazoline -2,4- diketone (399mg, 2.095mmol) is added into triethylamine (0.549mL, 3.14mmol) and 2, chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 6- bis- (describe conjunction in 3 step 2 of embodiment At solution of 500mg, the 2.095mmol) in methylene chloride (10mL) and the reaction mixture is stirred at room temperature 1 hour.It will The reaction mixture is quenched with ice cold water (50mL) and is extracted with ethyl acetate (2x 50mL).By combined organic layer with anhydrous Na2SO4It is dried, filtered and concentrated, obtains the chloro- 6- of 2- (4- (2,5- dioxoimidazolidin -1- base) piperidin-1-yl) -4- ethyl pyrrole Pyridine -3,5- dimethoxy nitrile (400mg, 39% yield), is gray solid.LCMS m/z=371.0 [M-H]-。
Step 4:2- ((3,5- dicyano -6- (4- (2,5- dioxoimidazolidin -1- base) piperidin-1-yl) -4- ethyl pyrrole Pyridine -2- base) sulfenyl) -2- phenyl-acetamides
By the chloro- 6- of 2- (4- (2,5- dioxoimidazolidin -1- base) piperidin-1-yl) -4- ethylpyridine -3,5- dimethoxy nitrile (400mg, 0.805mmol) and thioacetic acid potassium (184mg, 1.609mmol) are molten in n,N-Dimethylformamide (10mL) Liquid is stirred at room temperature 2 hours.Then potassium carbonate (222mg, 1.609mmol) and methanesulfonic acid 2- amino -2- oxo -1- phenyl is added Simultaneously the reaction mixture is stirred at room temperature for ethyl ester (describing synthesis, 388mg, 1.609mmol in 3 step 5 of embodiment) 16 hours.The reaction mixture is diluted with ethyl acetate (100mL) and washs organic layer HCl (1N, 2x 100mL).It will Organic layer anhydrous Na2SO4It dries, filters and evaporates, obtain black colloidal solid, it is purified with preparative-HPLC, is obtained 2- ((3,5- dicyano -6- (4- (2,5- dioxoimidazolidin -1- base) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides (160mg, 40% yield), are yellow solid.LCMS m/z=504.4 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.04 (s, 1H), 7.90 (s, 1H), 7.56-7.47 (m, 2H), 7.41-7.24 (m, 4H), 5.54 (s, 1H), 4.69 (d, J=13.37Hz, 2H), 4.24-4.09 (m, 1H), 3.88 (s, 2H), 3.20 (t, J=12.50Hz, 2H), 2.76 (q, J=7.67Hz, 2H), 2.37-2.22 (m, 2H), 1.75 (d, J=9.21Hz, 2H), 1.21 (t, J=7.56Hz, 3H)。
Embodiment 251:
4- amino -1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) piperidines -4- formamide
Step 1:4- amino piperidine -4- formamide
Under 0 DEG C of nitrogen, to 4- amino -1- benzyl piepridine -4- formamide (2g, 8.40mmol) in methanol (20mL) Agitating solution in be added palladium/carbon (10%, 2g, 1.879mmol).It is small that the reaction mixture is stirred to 5 under room temperature nitrogen atmosphere When.The reaction mixture is passed throughPad filtering, is washed with methanol (50mL).The filtrate is concentrated under reduced pressure, is obtained 4- amino piperidine -4- formamide (1.2g), is pale solid.LCMS m/z=144.2 [M+H]+。
Step 2:4- amino -1- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) piperidines -4- formamide
At 0 DEG C, to chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (in 3 step 2 of embodiment describe synthesis, 1.4g, 6.2mmol) addition triethylamine (1.726mL, 12.39mmol) in the solution in methylene chloride (15mL).After 2 minutes, Solution of the 4- amino piperidine -4- formamide (0.887g, 6.19mmol) in n,N-Dimethylformamide (15mL) is added simultaneously The mixture is stirred 10 minutes at 0 DEG C.The reaction mixture is quenched with water (50mL) and is extracted with DCM (2x 30mL).It will Combined organic layer is dried, filtered and is concentrated to dryness with anhydrous sodium sulfate.By the crude compound silica gel chromatography (100-200 mesh is eluted with 3-4% methanol/DCM), obtains 4- amino -1- (chloro- 3, the 5- dicyano -4- ethylpyridine -2- of 6- Base) piperidines -4- formamide (2.2g, 4.49mmol, 73% yield) is pink solid.LCMS m/z=333.1 [M+H]+。
Step 3:4- amino -1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl Pyridine -2- base) piperidines -4- formamide
(in 62 step 5 of embodiment conjunction is described to thioacetic acid S- (2- amino -2- oxo -1- phenylethyl) ester Be added in the agitating solution in n,N-Dimethylformamide (5mL) at 1.15g, 4.89mmol) potassium carbonate (1.014g, 7.34mmol) and 4- amino -1- (chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-) piperidines -4- formamide (2.186g, 4.40mmol) and by the mixture it is stirred at room temperature 14 hours.The reaction mixture is quenched with cold water (30mL) and uses EtOAc (2x 20mL) extraction.By combined organic layer anhydrous Na2SO4It dries, filters and is concentrated in vacuo.Raw product is passed through into silica gel Column chromatography purifying (100-200 mesh is eluted with 3-4% methanol/DCM), obtains 4- amino -1- (6- ((2- amino -2- oxo -1- Phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidines -4- formamide (95mg, 4% yield), for ash White solid.LCMS m/z=464.4 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.89 (s, 1H), 7.51 (d, J =7.02Hz, 2H), 7.43 (br s, 1H), 7.39-7.28 (m, 4H), 6.99 (br s, 1H), 5.53 (s, 1H), 4.31 (d, J =13.37Hz, 2H), 3.68-3.55 (m, 2H), 2.75 (q, J=7.38Hz, 2H), 2.12-1.90 (m, 4H), 1.49 (d, J= 13.59Hz, 2H), 1.21 (t, J=7.67Hz, 3H).
Embodiment 252:
2- ((3,5- dicyano -6- (4- (2,5- dioxo pyrrolidin -1- base) piperidin-1-yl) -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides
Step 1:1- (1- benzyl piepridine -4- base) pyrrolidine-2,5-dione
In room temperature, it is added in the solution in acetic acid (75mL) to dihydrofuran -2,5- diketone (2.5g, 24.98mmol) 1- benzyl piepridine -4- amine (4.75g, 24.98mmol).The reaction mixture is stirred 72 hours at 100 DEG C.Acetic acid is passed through into steaming Distillation is gone.Then the mixture is quenched with saturated sodium bicarbonate aqueous solution (100mL) and is extracted with DCM (100mL).This is had Machine is mutually dried, filtered and is concentrated with sodium sulphate.Raw product is purified with column chromatography, uses silica gel (100-200 mesh, with 100% Dichloromethane eluent).The pure fraction is concentrated under reduced pressure, the pale solid of (3.2g, 41% yield) is obtained.LCMS m/z= 273.16[M+H]+。
Step 2:1- (piperidin-4-yl) pyrrolidine-2,5-dione
To 1- (1- benzyl piepridine -4- base) pyrrolidines -2,5- diketone (3.2g, 10.35mmol) in methanol (100mL) Solution in be added and Pd-C (10%, 1.102g, 10.35mmol) and the mixture be placed under nitrogen atmosphere (balloon).This is anti- Mixture is answered to stir 24 hours under room temperature nitrogen atmosphere.The reaction mixture is passed throughFiltering, is washed with MeOH (20mL) It washs.The filtrate is concentrated and gained residue is purified with column chromatography, (is eluted with 5%MeOH/DCM) using neutral alumina. The pure fraction is concentrated under reduced pressure, the pale solid of (2.0g) is obtained.LCMS m/z=183.2 [M+H]+。
The chloro- 6- of step 3:2- (4- (2,5- dioxo pyrrolidin -1- base) piperidin-1-yl) -4- ethylpyridine -3,5- two Formonitrile HCN
At 0 DEG C, to chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (in 3 step 2 of embodiment describe synthesis, 500mg, 2.095mmol) addition triethylamine (0.549mL, 3.94mmol) in the solution in methylene chloride (10mL).2 minutes Afterwards, 1- (piperidin-4-yl) pyrrolidines -2,5- diketone (441mg, 2.095mmol) is added and stirs the reaction 5 minutes at 0 DEG C. The reaction mixture is quenched with ice cold water (20mL) and is extracted with ethyl acetate (2x 50mL).Combined organic layer is used Na2SO4It dries, filters and is concentrated, obtain raw product, it is purified with column chromatography, use silica gel (100-200 mesh, with 35% The hexanes of EtOAc).The pure fraction is concentrated under reduced pressure, the pale solid of (700mg, 88% yield) is obtained. LCMS m/z=372.2 [M+H]+。
Step 4:2- ((3,5- dicyano -6- (4- (2,5- dioxo pyrrolidin -1- base) piperidin-1-yl) -4- ethyl pyrrole Pyridine -2- base) sulfenyl) -2- phenyl-acetamides
To the chloro- 6- of 2- (4- (2,5- dioxo pyrrolidin -1- base) piperidin-1-yl) -4- ethylpyridine -3,5- dimethoxy nitrile (500mg, 1.324mmol) in the solution in n,N-Dimethylformamide (10mL) be added thioacetic acid potassium (303mg, 2.65mmol).The reaction mixture is stirred at room temperature 2 hours.It is added potassium carbonate (366mg, 2.65mmol), first is then added Sulfonic acid 2- amino -2- oxo -1- phenylethylester (describing synthesis, 320mg, 1.324mmol in 3 step 5 of embodiment) is simultaneously The reaction mixture is stirred at room temperature 16 hours.The reaction mixture is diluted with ice cold water (100mL) and with EtOAc (2x 100mL) extract.Combined organic layer is washed with HCl (1N, 2x 500mL), uses anhydrous Na2SO4It dries, filters and is concentrated.It will Raw product is purified with column chromatography, is used silica gel (100-200 mesh, 0-5%MeOH is in DCM as eluant, eluent).It is pure to collect this Fraction, concentration and drying, obtain 2- ((3,5- dicyano -6- (4- (2,5- dioxo pyrrolidin -1- base) piperidin-1-yl) -4- Ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides (250mg, 37% yield) are Light brown solid.LCMS m/z= 503.4[M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm7.89 (s, 1H), 7.54-7.49 (m, 2H), 7.41-7.26 (m, 4H), 5.54 (s, 1H), 4.68 (d, J=13.37Hz, 2H), 4.30-4.20 (m, 1H), 3.25-3.14 (m, 2H), 2.76 (q, J =7.60Hz, 2H), 2.61 (s, 4H), 2.35-2.22 (m, 2H), 1.70 (d, J=9.65Hz, 2H), 1.21 (t, J= 7.56Hz, 3H).
Embodiment 254
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides (isomers 1)
By racemic 2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyrrole Pyridine -2- base) sulfenyl) -2- phenyl-acetamides (synthesis, 302mg are described in embodiment 56) by chirality HPLC fractionation (IC 21x 250mm, 5 microns, MeOH is as eluant, eluent), obtain 2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- phenodiazines Trioxepane -1- base) pyridine -2- base) sulfenyl) and -2- phenyl-acetamides the first eluting diastereomer (isomers 1) (96.3mg, 95.8%ee).LCMS m/z=435.2 [M+H]+。1H NMR (400MHz, methanol-d4) δ ppm 7.52 (d, J= 1.27Hz, 2H) 7.41 (d, J=7.60Hz, 3H) 5.51 (s, 1H) 4.05 (s, 4H) 2.93 (d, J=7.60Hz, 2H) 2.77- 2.88 (m, 2H) 2.59-2.72 (m, 2H) 2.43 (s, 3H) 2.04-2.17 (m, 2H) 1.32 (t, J=7.60Hz, 3H).
Embodiment 255
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides (isomers 2)
Also from above-mentioned fractionation (embodiment 254), 2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- phenodiazines are obtained Trioxepane -1- base) pyridine -2- base) sulfenyl) and -2- phenyl-acetamides the second eluting diastereomer (isomers 2) (104.0mg, 95.8%ee).LCMS m/z=435.2 [M+H]+。1H NMR (400MHz, methanol-d4)δppm 7.50-7.57 (2H, m) 7.33-7.47 (3H, m) 5.51 (1H, s) 3.94-4.10 (4H, m) 2.93 (2H, d, J=7.60Hz) 2.86 (2H, Br.s.) 2.59-2.76 (2H, m) 2.42 (3H, s) 2.05-2.17 (2H, m) 1.32 (3H, t, J=7.60Hz).
Embodiment 256
2- ((3,5- dicyano -4- ethyl -6- (2- oxo -1- oxa- -3,8- diaza spiro [4.5] decyl- 8- yl) pyrrole Pyridine -2- base) sulfenyl) -2- phenyl-acetamides
The chloro- 4- ethyl -6- of step 1:2- (2- oxo -1- oxa- -3,8- diaza spiro [4.5] decyl- 8- yl) pyridine -3, 5- dimethoxy nitrile
By chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in 3 step 2 of embodiment, 1.5g, 6.64mmol), 1- oxa- -3,8- diaza spiro [4.5] decyl- 2- ketone (1.036g, 6.64mmol) and triethylamine (0.671g, Mixture 6.64mmol) stirs 15 hours at 25 DEG C.Solvent in vacuo is evaporated.Then DCM (50mL) and water (30mL) are added To the residue and organic layer is separated and is washed with brine, dried and concentrated.By residue silica gel chromatograph (PE/EA= It 2:1) purifies, obtains the chloro- 4- ethyl -6- of 2- (2- oxo -1- oxa- -3,8- diaza spiro [4.5] decyl- 8- yl) pyridine -3,5- Dimethoxy nitrile (800mg, 2.314mmol, 35% yield).LCMS m/z=368.0 [M+Na]+。
Step 2:2- ((3,5- dicyano -4- ethyl -6- (2- oxo -1- oxa- -3,8- diaza spiro [4.5] decyl- 8- Base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides
By the chloro- 4- ethyl -6- of 2- (2- oxo -1- oxa- -3,8- diaza spiro [4.5] decyl- 8- yl) pyridine -3,5- two Formonitrile HCN (300mg, 0.868mmol) and thioacetic acid potassium (198mg, 1.735mmol) add to n,N-Dimethylformamide (30mL). The mixture is stirred 2 hours.Then methanesulfonic acid 2- amino -2- oxo -1- phenylethylester is added (in 3 step 5 of embodiment Describe synthesis, 398mg, 1.735mmol) and stir the mixture 15 hours.The solvent in vacuo is evaporated.Then it is added DCM (30mL) and water (20mL).Organic layer is separated, is washed with brine, is dried and concentrated.By residue preparative-HPLC Purifying, obtains 2- ((3,5- dicyano -4- ethyl -6- (2- oxo -1- oxa- -3,8- diaza spiro [4.5] decyl- 8- yl) pyrrole Pyridine -2- base) sulfenyl) -2- phenyl-acetamides (100mg, 0.210mmol, 24% yield).LCMS m/z=477.1 [M+H]+。1H NMR (400MHz, DMSO-d6): δ ppm 7.92 (s, 1H), 7.62 (s, 1H), 7.53-7.51 (m, 2H), 7.41-7.34 (m, 4H), 5.54 (s, 1H), 4.24-4.17 (m, 2H), 3.64 (t, 2H), 3.31 (s, 2H), 2.78-2.74 (m, 2H), 1.87- 1.94 (m, 4H), 1.23 (t, 3H).
Embodiment 258:
1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) -4- Hydroxy piperidine -4- formamide
Step 1:1- benzyl -4- hydroxy piperidine -4- formamide
Under 0 DEG C of nitrogen, to 1- benzyl -4- hydroxy piperidine -4- formonitrile HCN (1g, 3.56mmol) at methylene chloride (10mL) In agitating solution in H is added2SO4(3mL, 56.3mmol).The reaction mixture is stirred at room temperature 2 hours.Then by hydrogen-oxygen Change ammonium (28%, 7mL, 50.3mmol) to be added at 0 DEG C and the mixture is stirred at room temperature 14 hours.The reaction mixture is used DCM (2x 20mL) extraction.Combined organic layer is dried, filtered and is concentrated under reduced pressure with anhydrous sodium sulfate, 1- benzyl -4- is obtained Hydroxy piperidine -4- formamide (750mg), is pale solid.LCMS m/z=235.1 [M+H]+。
Step 2:4- hydroxy piperidine -4- formamide
Under 0 DEG C of nitrogen, to 1- benzyl -4- hydroxy piperidine -4- formamide (740mg, 3.14mmol) at methanol (15mL) In agitating solution in be added palladium/carbon (10%, 740mg, 0.695mmol).The reaction mixture is stirred under room temperature nitrogen atmosphere It mixes 5 hours.The reaction mixture is passed throughFiltering, uses methanol rinse.The filtrate is concentrated under reduced pressure, 4- is obtained Hydroxy piperidine -4- formamide (350mg), is pale solid.1H NMR (400MHz, DMSO-d6): δ ppm7.11 (s, 1H), 6.97 (s, 1H), 5.05 (s, 1H), 2.78-2.63 (m, 4H), 1.76 (td, J=12.39,5.26Hz, 2H), 1.31 (d, J= 11.62Hz 2H).
Step 3:1- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) -4- hydroxy piperidine -4- formamide
At 0 DEG C, to chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (in 3 step 2 of embodiment describe synthesis, 550mg, 2.433mmol) addition triethylamine (0.678mL, 4.87mmol) in the agitating solution in methylene chloride (5mL).2 points The solution of 4- hydroxy piperidine -4- formamide (351mg, 2.433mmol) in n,N-Dimethylformamide (5mL) is added in Zhong Hou And the reaction mixture is stirred 10 minutes at 0 DEG C.The reaction mixture is diluted with water (20mL) and with DCM (2x 10mL) Extraction.Combined organic layer is dried, filtered and is concentrated in vacuo with anhydrous sodium sulfate.The crude product column chromatography of acquisition is pure Change, using silica gel (100-200 mesh is eluted with 3-4% methanol/DCM), obtains 1- (chloro- 3, the 5- dicyano -4- ethylpyridine-of 6- 2- yl) -4- hydroxy piperidine -4- formamide (800mg, 97% yield) is pink solid.LCMS m/z=334.1 [M+H]+。
Step 4:1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) -4- hydroxy piperidine -4- formamide
In room temperature, to 1- (chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-) -4- hydroxy piperidine -4- formamide (400mg, 1.174mmol) in the agitating solution in n,N-Dimethylformamide (5mL) be added thioacetic acid potassium (268mg, 2.349mmol) and in mutually synthermal stirring 2 hours.In room temperature, be added into the reaction mixture potassium carbonate (325mg, 2.349mmol) and methanesulfonic acid 2- amino -2- oxo -1- phenylethylester (describe synthesis in 3 step 5 of embodiment, 272mg, 1.174mmol) and be stirred at room temperature 14 hours.The reaction mixture water (50mL) is diluted and uses ethyl acetate (2x 30mL) extraction.Combined organic layer is dried, filtered and is concentrated in vacuo with anhydrous sodium sulfate, crude product is obtained.It will obtain Crude product purified with column chromatography, using silica gel (100-200 mesh is eluted with the DCM solution of 3-4% methanol), obtain 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) -4- hydroxy piperidine -4- first Amide (260mg, 47% yield), is pale solid.LCMS m/z=465.5 [M+H]+。1H NMR (400MHz, DMSO- d6) δ ppm 7.89 (s, 1H), 7.55-7.47 (m, 2H), 7.42-7.26 (m, 5H), 7.15 (br s, 1H), 5.53 (s, 2H), 4.44 (d, J=9.87Hz, 2H), 3.50-3.36 (m, 2H), 2.76 (q, J=7.45Hz, 2H), 2.05-1.91 (m, 2H), 1.62 (d, J=13.81Hz, 2H), 1.21 (t, J=7.56Hz, 3H).
Embodiment 259:
Carbamic acid 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) azetidine -3- base ester
Step 1: carbamic acid 1- dibenzo-p-methyl-aza-cyclobutane -3- base ester
At 0 DEG C, to 1- dibenzo-p-methyl-aza-cyclobutane -3- alcohol (2g, 8.36mmol) stirring in ethyl acetate (50mL) It mixes and 2,2,2- tribromo-acetyl base ester (1.25mL, 8.36mmol) of isocyanic acid is added in solution and stirs the mixture 1 hour.So The reaction mixture is concentrated under reduced pressure afterwards.Gained residue is dissolved in methanol (50mL) and water (4mL) and sodium formate is added (0.568g, 8.36mmol).The reaction mixture is stirred at room temperature 24 hours.The reaction mixture is concentrated under reduced pressure, Then the residue is diluted with EtOAc (70mL).By organic layer saturated sodium bicarbonate aqueous solution (20mL), saturated brine (10mL) washing, is dried, filtered and is concentrated under reduced pressure with anhydrous sodium sulfate.Gained residue is ground with ether (20mL), is obtained Carbamic acid 1- dibenzo-p-methyl-aza-cyclobutane -3- base ester (900mg, 34% yield), is pale solid.LCMS m/z= 283.1[M+H]+。
Step 2: carbamic acid 1- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) azetidine -3- base ester
Under 0 DEG C of nitrogen atmosphere, to carbamic acid 1- dibenzo-p-methyl-aza-cyclobutane -3- base ester (900mg, 2.82mmol) Pd/C (10%, 600mg, 0.564mmol) is added in the agitating solution in methanol (10mL).By the reaction mixture in room temperature It is stirred 16 hours under nitrogen atmosphere.The reaction mixture is passed throughFiltering, is washed with methanol (20mL).The filtrate is existed The lower concentration of decompression, is diluted and is stirred 30 minutes with HCl (2N, 20mL).The solution is concentrated under reduced pressure, carbamic acid azacyclo- is obtained Butane -3- base ester hydrochloride (400mg), is pale solid, which is used in next step.At 0 DEG C, to 2,6- bis- Chloro- 4- ethylpyridine -3,5- dimethoxy nitrile (describing synthesis, 500mg, 2.095mmol in 3 step 2 of embodiment) is in tetrahydro furan Carbamic acid azetidine -3- base ester hydrochloride (320mg, 2.095mmol), water are added in the agitating solution muttered in (10mL) (10mL) and sodium bicarbonate aqueous solution (176mg, 2.095mmol).The reaction mixture is stirred at room temperature 1 hour.This is anti- Mixture is answered to be concentrated under reduced pressure and dilute gained residue water (30mL) and extracted with ethyl acetate (2x 120mL).It will Combined organic layer anhydrous Na2SO4It dries, filters, be concentrated under reduced pressure and dry, obtain carbamic acid 1- (chloro- 3, the 5- dicyan of 6- Base -4- ethylpyridine -2- base) azetidine -3- base ester (430mg).LCMS m/z=303.9 [M-H]-。
Step 3: carbamic acid 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- second Yl pyridines -2- base) azetidine -3- base ester
In room temperature, to carbamic acid 1- (chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-) azetidine -3- base Thioacetic acid potassium is added in the agitating solution in n,N-Dimethylformamide (10mL) in ester (420mg, 1.038mmol) (237mg, 2.076mmol) and in mutually synthermal stirring 2 hours.Potassium carbonate (215mg, 1.557mmol) and first is added in room temperature Sulfonic acid 2- amino -2- oxo -1- phenylethylester (describing synthesis, 308mg, 1.246mmol in 3 step 5 of embodiment) is simultaneously The reaction mixture is stirred at room temperature 16 hours.The reaction mixture is diluted with cold water (50mL) and with EtOAc (2x 100mL) extract.By combined organic layer Na2SO4It dries, filters and is concentrated under reduced pressure, obtain the crude compound.By the thick object Matter is purified by column chromatography, using silica gel (100-200 mesh, eluted with 100%EtOAc), is obtained brown solid, is dissolved in The DCM solution (50mL) of 10%MeOH.Charcoal (500mg) is added and heats the mixture 5 minutes at 50 DEG C, then passes throughPad filtering, is washed with 10%MeOH in DCM (25mL).The filtrate is concentrated under reduced pressure, carbamic acid 1- is obtained (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) azetidine -3- Base ester (217mg, 48% yield), is pale solid.LCMS m/z=437.5 [M+H]+。1H NMR (400MHz, DMSO- d6) δ ppm 7.86 (s, 1H), 7.56-7.48 (m, 2H), 7.40-7.32 (m, 3H), 7.26 (s, 1H), 6.92-6.71 (m, 2H), 5.57 (s, 1H), 5.18-5.10 (m, 1H), 4.80-4.66 (m, 2H), 4.29 (d, J=8.99Hz, 2H), 2.70 (q, J =7.53Hz, 2H), 1.18 (t, J=7.67Hz, 3H).
Embodiment 260:
2- ((3,5- dicyano -6- (4- (2,4- dioxo oxazolidine -3- base) piperidin-1-yl) -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides
Step 1:3- (1- benzyl piepridine -4- base) oxazolidine -2,4- diketone
In room temperature, it is added in the solution in DMF (40mL) to 2- hydroxy methyl acetate (1.298mL, 16.82mmol) Simultaneously the reaction mixture is stirred at room temperature 2 hours for 1,1 '-carbonyl dimidazoles (CDI, 2.73g, 16.82mmol).Thereto plus Enter 1- benzyl piepridine -4- amine (3.44mL, 16.82mmol) and stirs the reaction mixture 16 hours at 60 DEG C.By the reaction Mixture is cooled to room temperature, and water is added and stirs the mixture 10 minutes.The solid by filtration of precipitation is collected and is dried, Obtain 3- (1- benzyl piepridine -4- base) oxazolidine -2,4- diketone (1.8g, 37% yield).LCMS m/z=275.2 [M+H]+。
Step 2:3- (piperidin-4-yl) oxazolidine -2,4- diketone
At 0 DEG C, to 3- (1- benzyl piepridine -4- base) oxazolidine -2,4- diketone (1.8g, 6.22mmol) in methanol Palladium dydroxide/carbon (20%, 600mg, 0.854mmol) is added in solution in (60mL).On Paar oscillator, by the reaction Mixture stirs 12 hours under room temperature nitrogen atmosphere.The reaction mixture is passed throughFiltering, is washed with MeOH (20mL) It washs.The filtrate is concentrated under reduced pressure, the crude product is obtained.The crude product column chromatography is purified into (neutral alumina, with 5% The DCM solution of MeOH elutes).The pure fraction is concentrated under reduced pressure, required 3- (piperidin-4-yl) oxazolidine -2,4- bis- is obtained Ketone (340mg, 26% yield) is canescence viscous solid.LCMS m/z=185.1 [M+H]+。
The chloro- 6- of step 3:2- (4- (2,4- dioxo oxazolidine -3- base) piperidin-1-yl) -4- ethylpyridine -3,5- two Formonitrile HCN
At 0 DEG C, to chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (in 3 step 2 of embodiment describe synthesis, 400mg, 1.752mmol) addition triethylamine (0.488mL, 3.50mmol) in the solution in methylene chloride (15mL).2 minutes Afterwards, it is slowly added to 3- (piperidin-4-yl) oxazolidine -2,4- diketone (323mg, 1.752mmol) at 0 DEG C, continues 20 minutes, and Mutually synthermal stirring 6 hours.The reaction mixture is quenched with ice water (20mL) and is extracted with DCM (2x 50mL).By merging Organic layer is dried, filtered and is concentrated with sodium sulphate, obtains the thick material, it is used flash column chromatography, uses silica gel (60- 120 mesh are eluted with the petroleum ether solution of 50% ethyl acetate), obtain the chloro- 6- of 2- (4- (2,4- dioxo oxazolidine -3- base) piperazine Pyridine -1- base) -4- ethylpyridine -3,5- dimethoxy nitrile (200mg, 30% yield) is pale solid.LCMS m/z=374.3 [M+H]+。
Step 4:2- ((3,5- dicyano -6- (4- (2,4- dioxo oxazolidine -3- base) piperidin-1-yl) -4- ethyl pyrrole Pyridine -2- base) sulfenyl) -2- phenyl-acetamides
By the chloro- 6- of 2- (4- (2,4- dioxo oxazolidine -3- base) piperidin-1-yl) -4- ethylpyridine -3,5- dimethoxy nitrile The solution of (180mg, 0.470mmol) and thioacetic acid potassium (107mg, 0.941mmol) in n,N-Dimethylformamide (5mL) It is stirred at room temperature 2 hours.Then potassium carbonate (130mg, 0.941mmol) and methanesulfonic acid 2- amino -2- oxo -1- phenyl second is added The reaction mixture is simultaneously stirred at room temperature 16 by base ester (describing synthesis, 218mg, 0.941mmol in 3 step 5 of embodiment) Hour.The reaction mixture is diluted with ethyl acetate (100mL) and is washed with HCl (1N, 2x 100mL).By organic layer nothing Water Na2SO4It dries, filters and evaporates, obtain crude product (300mg), be black colloidal solid.The thick material is passed through into silica gel It purifies (100-200 mesh, with the hexanes of 50% ethyl acetate).By pure fraction vacuum concentration and drying, 2- is obtained ((3,5- dicyano -6- (4- (2,4- dioxo oxazolidine -3- base) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides (30mg, 12% yield), are pale solid.LCMS m/z=505.5 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.90 (br s, 1H), 7.52 (d, J=7.02Hz, 2H), 7.44-7.24 (m, 4H), 5.55 (s, 1H), 4.79 (s, 2H), 4.68 (d, J=12.06Hz, 2H), 4.26-4.17 (m, 1H), 3.26-3.19 (m, 2H), 2.83-2.71 (m, 2H), 2.21 (d, J=11.18Hz, 2H), 1.87 (d, J=12.72Hz, 2H), 1.21 (t, J=7.78Hz, 3H).
Embodiment 261:
3- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) amino) -2- hydroxy-2-methyl propionamide
Step 1:3- ((the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) (methyl) amino) -2- hydroxy-2-methyl Propionamide
By chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in 3 step 2 of embodiment, 0.513g, 2.270mmol), 2- hydroxy-2-methyl -3- (methylamino) propionamide (0.3g, 2.270mmol) and triethylamine (0.230g, 2.270mmol) it is dissolved in DCM (5mL).The mixture is stirred at room temperature 12 hours.The mixture is diluted with DCM and uses salt water Washing.Organic layer dries and concentrates.By the residue column purification, 3- ((chloro- 3, the 5- dicyano -4- ethylpyridine-of 6- is obtained 2- yl) (methyl) amino) -2- hydroxy-2-methyl propionamide (280mg, 0.870mmol, 38% yield).LCMS m/z=322 [M+H]+。
Step 2:3- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) (methyl) amino) -2- hydroxy-2-methyl propionamide
By 3- ((the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) (methyl) amino) -2- hydroxy-2-methyl propionyl Amine (280mg, 0.870mmol) and thioacetic acid potassium (199mg, 1.740mmol) are dissolved in n,N-Dimethylformamide (3mL).It will The mixture is stirred at room temperature 1 hour, and potassium carbonate (241mg, 1.740mmol) and methanesulfonic acid 2- amino -2- oxo-is then added 1- phenylethylester (describes synthesis, 399mg, 1.74mmol in 3 step 5 of embodiment).The mixture is stirred at room temperature It 12 hours, then filters.The filtrate is concentrated and preparative-HPLC is used to purify, obtains 3- ((6- ((2- amino -2- oxo -1- Phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) amino) -2- hydroxy-2-methyl propionamide (40mg, 0.088mmol, 10% yield).LCMS m/z=453.1 [M+H]+。1H NMR (400MHz, DMSO-d6)δppm 7.80 (s, 1H), 7.52-7.49 (m, 4H), 7.43-7.29 (m, 4H), 5.90 (s, 0.5H), 5.76 (s, 0.5H), 5.73- 5.71 (m, 1H), 4.59 (d, J=14.3Hz, 0.5H), 4.44 (d, J=14.3Hz, 0.5H), 3.98 (d, J=14.1Hz, 0.5H), 3.80 (d, J=14.2Hz, 0.5H), 3.46 (s, 3H), 2.77-2.75 (m, 2H), 1.31-1.18 (m, 3H), 1.23- 1.18 (m, 3H).
Embodiment 262
2- ((3,5- dicyano -4- ethyl -6- (3- (hydroxymethyl) azetidine -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides
The chloro- 4- ethyl -6- of step 1:2- (3- (hydroxymethyl) azetidine -1- base) pyridine -3,5- dimethoxy nitrile
To chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in 3 step 2 of embodiment, 1g, 4.42mmol) in the solution in methylene chloride (50mL) be added azetidine -3- base methanol (0.385g, 4.42mmol) and TEA (1.233mL, 8.85mmol).Then the reaction mixture is stirred into 30min.The mixture is washed with water (2x 50mL) It washs.Combined organic layer is concentrated, raw product (1g) is obtained, is yellow solid, is directly used in next step.LCMS M/z=277.0 [M+H]+。
Step 2:2- ((3,5- dicyano -4- ethyl -6- (3- (hydroxymethyl) azetidine -1- base) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides
To the chloro- 4- ethyl -6- of 2- (3- (hydroxymethyl) azetidine -1- base) pyridine -3,5- dimethoxy nitrile (1g, Thioacetic acid potassium (0.413g, 3.61mmol) 3.61mmol) is added in the solution in n,N-Dimethylformamide (2mL).It will The reaction mixture stirs 2 hours, and potassium carbonate (0.499g, 3.61mmol) and methanesulfonic acid 2- ammonia are then added into the mixture Base -2- oxo -1- phenylethylester (describing synthesis, 0.828g, 3.61mmol in 3 step 5 of embodiment).The reaction is mixed Object is closed to be stirred overnight.The reaction mixture is diluted with ethyl acetate (50mL) and is washed with salt water (5x50mL).By organic layer Concentration, then which is purified on a silica gel column, is eluted with DCM/MeOH, obtain 300mg white solid.It should by a part Material (100mg) is further purified with preparative-HPLC, obtains 2- ((3,5- dicyano -4- ethyl -6- (3- (hydroxymethyl) Azetidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides (20mg).LCMS m/z=408 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.88 (s, 1H), 7.52 (d, J=7.2Hz, 2H), 7.43-7.19 (m, 4H), 5.57 (s, 1H), 4.93 (t, J=4.9Hz, 1H), 4.50-4.15 (m, 4H), 3.62 (t, J=5.1Hz, 2H), 2.84 (s, 1H), 2.75- 2.62 (m, 2H), 1.20 (dd, J=19.9,12.5Hz, 3H).
Embodiment 263:
2- (3,5- dicyano -4- ethyl -6- (piperazine -1- base) pyridine -2- base sulfenyl) -2- (thiene-3-yl) acetamide
Step 1:2- (thiene-3-yl) -2- (trimethyl silyl oxygroup) acetonitrile
Thiophene -2-formaldehyde (2.8g, 25mmol) and trimethylsilyl cyanide (2.97g, 30mmol) are dissolved in chloroform (5mL). The solution is cooled down in cold bath (10 DEG C) and zinc iodide (II) (0.8g, 2.5mmol) is added.It is after stirring 8 hours, this is molten Liquid Et2O (100mL) is diluted and is washed with sodium thiosulfate solution (50mL) and saturated sodium bicarbonate aqueous solution (50mL). The organic solution is dried, filtered and evaporated with magnesium sulfate, 2- (thiophene -2- base) -2- ((trimethyl silyl) oxygen is obtained Base) acetonitrile (5g, 23.66mmol, 95% yield).1H NMR (400MHz, CDCl3) δ ppm7.44 (s, 1H), 7.40 (dd, J= 5.0,3.0Hz, 1H), 7.17 (d, J=5.0Hz, 1H), 5.59 (s, 1H), 0.25 (s, 9H).
Step 2:2- hydroxyl -2- (thiene-3-yl) acetamide
To stir under nitrogen at room temperature 2- (thiene-3-yl) -2- ((trimethyl silyl) oxygroup) acetonitrile (1g, 4.73mmol), chlorination is added in the solution in tetrahydrofuran (12mL) and water (4mL) in acetamide (1.174g, 19.87mmol) Palladium (II) (0.084g, 0.47mmol).The reaction mixture is stirred at room temperature overnight.The reaction mixture is filtered and should Filtrate concentration.The residue is added into silicagel column and (uses CH2Cl2/ MeOH elution, the fraction of collection: DCM/MeOH (15:1-10: 1) 2- hydroxyl -2- (thiene-3-yl) acetamide (600mg)), is obtained, is light yellow solid.1H NMR (400MHz, DMSO- d6) δ ppm 7.45 (dd, J=4.9,3.0Hz, 1H), 7.37 (d, J=2.9Hz, 1H), 7.11 (d, J=4.9Hz, 1H), 6.68 (s, 2H), 4.91 (s, 1H).
Step 3: methanesulfonic acid 2- amino -2- oxo -1- (thiene-3-yl) ethyl ester
To 2- hydroxyl -2- (thiene-3-yl) acetamide (520mg, 3.31mmol) and triethylamine stirred at 0 DEG C Methane sulfonyl chloride (417mg, 3.64mmol) is added dropwise in the solution in methylene chloride (10mL) in (502mg, 4.96mmol).It should Reaction mixture is stirred at room temperature 2 hours.The solvent is removed and raw product silica gel column purification (is used into CH2Cl2/ MeOH is washed It is de-), obtain methanesulfonic acid 2- amino -2- oxo -1- (thiene-3-yl) ethyl ester (118mg, 0.50mmol).1H NMR (400MHz, DMSO-d6) δ ppm 7.79 (s, 1H), 7.61 (d, J=2.0Hz, 1H), 7.55 (dd, J=5.0,3.0Hz, 1H), 7.47 (s, 1H), 7.21 (dd, J=5.0,1.0Hz, 1H), 5.58 (s, 1H), 3.34 (s, 3H).
Step 4:4- (6- (2- amino -2- oxo -1- (thiene-3-yl) ethylsulfanyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperazine -1- t-butyl formate
To 4- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of the 6-) piperazine -1- formic acid uncle stirred in air at room temperature Butyl ester (synthesis, 189mg, 0.503mmol are described in embodiment 176, step 1) and thioacetic acid potassium (57.4mg, Triethylamine (0.210mL, 1.509mmol) 0.503mmol) is added dropwise in the solution in n,N-Dimethylformamide (10mL), holds It is 1 minute continuous.The reaction mixture is stirred at room temperature 2 hours.Methanesulfonic acid 2- amino -2- oxygen is added into the reaction mixture Simultaneously gained mixture is stirred at room temperature 1 day for generation -1- (thiene-3-yl) ethyl ester (118mg, 0.50mmol).The solvent is removed It goes and the residue is washed with water.Raw product is added into silicagel column and uses CH2Cl2/ MeOH elution, obtains 4- (6- ((2- ammonia Base -2- oxo -1- (thiene-3-yl) ethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) the tertiary fourth of piperazine -1- formic acid Ester (150mg, 0.29mmol, 58% yield).1H NMR (300MHz, CDCl3) δ 7.36 (m, 3H), 7.15 (m, 2H), 5.45 (s, 1H), 3.89 (m, 4H), 3.58 (m, 4H), 2.91 (q, J=7.6Hz, 2H), 1.46 (s, 9H), 1.32 (t, J=7.6Hz, 3H).
Step 5:2- (3,5- dicyano -4- ethyl -6- (piperazine -1- base) pyridine -2- base sulfenyl) -2- (thiene-3-yl) Acetamide
To 4- (6- ((2- amino -2- oxo -1- (thiene-3-yl) ethyl) the sulfenyl) -3,5- dicyan stirred at 0 DEG C Base -4- ethylpyridine -2- base) solution of the piperazine -1- t-butyl formate (150mg, 0.29mmol) in methylene chloride (10mL) Middle dropwise addition trifluoroacetic acid (2mL, 26.0mmol).The reaction mixture is stirred at room temperature 2 hours.The solvent is removed and should Residue is dissolved in 2mL MeOH.The saturated solution of sodium carbonate is added to adjust pH to 13, then the MeOH is removed under reduced pressure simultaneously The mixture is extracted with dichloromethane and is concentrated.Thick material preparative-TLC is purified, 2- ((3,5- dicyanos-are obtained 4- ethyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- (thiene-3-yl) acetamide (61mg, 0.15mmol, 52%), It is white solid.LCMS m/z=413.2 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.88 (s, 1H), 7.59- 7.50 (m, 2H), 7.34 (s, 1H), 7.18 (d, J=4.9Hz, 1H), 5.62 (s, 1H), 3.95-3.72 (m, 4H), 2.92- 2.76 (m, 4H), 2.76 (d, J=7.6Hz, 2H), 1.23 (d, J=3.2Hz, 1H), 1.21 (t, J=7.6Hz, 3H).
Embodiment 264:
(S) -2- amino -3 Methylbutanoic acid 2- ((1- (6- ((4- (acetylamino methyl) benzyl) sulfenyl) -3,5- dicyan Base -4- ethylpyridine -2- base) piperidin-4-yl) oxygroup) ethyl ester
Step 1:N- (4- (((3,5- dicyano -4- ethyl -6- (4- (2- hydroxyl-oxethyl) piperidin-1-yl) pyridine -2- Base) sulfenyl) methyl) benzyl) acetamide
To the chloro- 4- ethyl -6- of 2- (4- (2- hydroxyl-oxethyl) piperidin-1-yl) pyridine -3,5- dimethoxy nitrile (in embodiment 224, describe synthesis, 1g, 2.99mmol in step 3) be added in the solution in n,N-Dimethylformamide (10mL) it is thio Potassium acetate (0.512g, 4.48mmol).The mixture is stirred at room temperature 2 hours, K is then used2CO3(0.826g, 5.97mmol) Processing.Gained mixture is stirred at room temperature 1 hour, then with N- (4- (bromomethyl) benzyl) acetamide (0.868g, It 3.58mmol) handles and is stirred at room temperature overnight the mixture.Gained mixture is concentrated in vacuo, then uses the residue EtOAc (100mL) dilution.The organic phase is washed with water (25mL x 2) and saturated brine (25mL), with sodium sulphate it is dry and It is evaporated in vacuo, obtains raw product, be brown solid.Raw product is added into silicagel column and uses CH2Cl2/ MeOH (20:1) is washed It is de-, obtain N- (4- (((3,5- dicyano -4- ethyl -6- (4- (2- hydroxyl-oxethyl) piperidin-1-yl) pyridine -2- base) sulfenyl) Methyl) benzyl) acetamide (0.8g).LCMS m/z=494.1 [M+H]+。
Step 2:(S) -2- ((tertbutyloxycarbonyl) amino) -3 Methylbutanoic acid 2- ((1- (6- ((4- (acetylamino methyl) Benzyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl) oxygroup) ethyl ester
In room temperature, to 1H- benzo [d] [1,2,3] triazole -4- alcohol (109mg, 0.810mmol), (S) -2- ((tertiary fourth oxygen Carbonyl) amino) -3 Methylbutanoic acid (352mg, 1.621mmol) and N1- ((ethylimino) methylene)-N3, N3- dimethyl Propyl- 1,3- diamines (377mg, 2.431mmol) be added in the solution in methylene chloride (20mL) triethylamine (246mg, 2.431mmol).The mixture is stirred at room temperature 30 minutes, N- (4- (((3,5- dicyano -4- ethyl -6- (4- are then used (2- hydroxyl-oxethyl) piperidin-1-yl) pyridine -2- base) sulfenyl) methyl) benzyl) acetamide (200mg) processing.Gained is mixed Object is stirred at room temperature overnight, and is then concentrated in vacuo.The residue is added into silicagel column and uses CH2Cl2/ MeOH (50:1) elution, obtains To (S) -2- ((tertbutyloxycarbonyl) amino) -3 Methylbutanoic acid 2- ((1- (6- ((4- (acetylamino methyl) benzyl) sulfenyl) -3, 5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl) oxygroup) ethyl ester (300mg).LCMS m/z=715.2 [M+Na]+。
Step 3:(S) -2- amino -3 Methylbutanoic acid 2- ((1- (6- ((4- (acetylamino methyl) benzyl) sulfenyl) -3, 5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl) oxygroup) ethyl ester
To (S) -2- ((tertbutyloxycarbonyl) amino) -3 Methylbutanoic acid 2- ((1- (6- ((4- (acetylamino methyl) benzyl Base) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl) oxygroup) ethyl ester (280mg) is in methylene chloride 2,2,2- trifluoroacetic acids (922mg, 8.08mmol) are added in solution in (5mL).It is small that gained mixture is stirred at room temperature 2 When, then it is concentrated in vacuo.The residue is diluted with EtOAc (50mL) and with saturated sodium bicarbonate aqueous solution (50mL), water The washing of (25mL) and saturated brine (25mL).Organic layer with sodium sulphate drying and is evaporated in vacuo, raw product is obtained, for Huang Color solid.Raw product is added into silicagel column and is eluted with DCM/MeOH (30:1), (S) -2- amino -3 Methylbutanoic acid 2- is obtained ((1- (6- ((4- (acetylamino methyl) benzyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl) oxygen Base) ethyl ester (120mg, 0.198mmol).LCMS m/z=593.2 [M+H]+。1H NMR (400MHz, DMSO-d6)δppm 8.36-8.30 (m, 1H), 7.35 (d, J=8.0Hz, 2H), 7.21 (d, J=8.0Hz, 2H), 4.47 (s, 2H), 4.32-4.19 (m, 3H), 4.17-4.04 (m, 3H), 3.71-3.58 (m, 5H), 3.16 (d, J=5.3Hz, 1H), 2.77 (q, J=7.6Hz, 2H), 2.24-1.76 (m, 8H), 1.63-1.50 (m, 2H), 1.22 (dd, J=13.0,5.4Hz, 3H), 0.86 (dd, J= 15.4,6.8Hz, 6H).
Embodiment 266
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (5- picoline -3- base) acetamide
Step 1:2- hydroxyl -2- (5- picoline -3- base) acetamide
Front three is added in the solution in methylene chloride (20mL) to 5- picoline -3- formaldehyde (1.0g, 8.26mmol) Base cyanogen silane (1.239mL, 9.91mmol).The mixture is stirred at room temperature overnight.The mixture is concentrated, light brown is obtained Oil.By above-mentioned crude product with dense H2SO4(6mL, 113mmol) is handled 4 hours, and then the reaction mixture is poured into ice and made Use NH4OH adjusts pH to 9.The reaction mixture is concentrated with silica gel, with silica gel column purification (40g column, makes With 0-10%MeOH/DCM), obtaining 2- hydroxyl -2- (5- picoline -3- base) acetamide, (636mg, 3.83mmol, 46% are produced Rate), it is yellow oil.LCMS m/z=166.9 [M+H]+。
Step 2: methanesulfonic acid 2- amino -1- (5- picoline -3- base) -2- oxoethyl ester
To 2- hydroxyl -2- (5- picoline -3- base) acetamide (636mg, 3.83mmol) and TEA (1.067mL, Methane sulfonyl chloride (0.358mL, 4.59mmol) 7.65mmol) is added in the solution in tetrahydrofuran (20mL).By the mixing Object is stirred at room temperature overnight.The reaction mixture is concentrated with silica and use silica gel column purification (24g Column uses 0-10%MeOH/DCM), obtain methanesulfonic acid 2- amino -1- (5- picoline -3- base) -2- oxoethyl ester (798mg, 3.27mmol, 85% yield), is yellow solid.LCMS m/z=245.1 [M+H]+。
Step 3:2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) -2- (5- picoline -3- base) acetamide
By 4- ethyl -2- sulfydryl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -3,5- dimethoxy nitrile (in reality Apply example 69, synthesis, 107mg, 0.354mmol described in step 1), methanesulfonic acid 2- amino -1- (5- picoline -3- base) -2- The reaction mixture of oxoethyl ester (72mg, 0.295mmol) and TEA (0.082mL, 0.590mmol) in DMF (3mL) exists It is stirred overnight at room temperature.By the reaction mixture with silica (12g column) purifying, use 10-20% MeOH/DCM is as eluant, eluent.Obtained fractions are concentrated and are used the second silica gel column purification (12g column, use 20%MeOH/DCM), Obtain 2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (5- picoline -3- base) acetamide (51mg, 0.113mmol, 39% yield), is pale solid.LCMS m/z= 450.2[M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 1.21 (t, J=7.6Hz, 3H), 1.86-2.00 (m, 2H), 2.26 (s, 3H), 2.31 (s, 3H), 2.41-2.48 (m, 1H), 2.52-2.63 (m, 2H), 2.63-2.72 (m, 1H), 2.77 (q, J=7.66Hz, 2H), 3.80-4.01 (m, 4H), 5.56 (s, 1H), 7.45 (s, 1H), 7.70 (s, 1H), 8.00 (s, 1H), 8.38 (d, J=1.3Hz, 1H), 8.50 (d, J=2.0Hz, 1H).
Embodiment 267
(S) -2- amino -3 Methylbutanoic acid 2- ((6- ((4- (acetylamino methyl) benzyl) sulfenyl) -3,5- dicyano - 4- ethylpyridine -2- base) (methyl) amino) ethyl ester, trifluoroacetate
Step 1:N- (4- (((3,5- dicyano -4- ethyl -6- ((2- hydroxyethyl) (methyl) amino) pyridine -2- base) Sulfenyl) methyl) benzyl) acetamide
To the chloro- 4- ethyl -6- of 2- ((2- hydroxyethyl) (methyl) amino) pyridine -3,5- dimethoxy nitrile (in embodiment 147, Synthesis, 264mg, 0.997mmol are described in step 1) be added in the solution in n,N-Dimethylformamide (15mL) it is thio Potassium acetate (171mg, 1.496mmol), is then added K2CO3(414mg, 2.99mmol).The mixture is small in 25 DEG C of stirrings 16 When.Then K is added2CO3(474mg, 3.43mmol) and N- (4- (bromomethyl) benzyl) acetamide (435mg, 1.258mmol).It will The mixture stirs 16 hours at 25 DEG C.The mixture is poured into water (15mL) and is extracted with ethyl acetate (25mL x 2). Combined organic layer is concentrated, the residue column chromatography is then purified into (DCM/MeOH=30:1).Required fraction is concentrated And recrystallize obtained solid from methanol, obtain N- (4- (((3,5- dicyano -4- ethyl -6- ((2- hydroxyethyl) (first Base) amino) pyridine -2- base) sulfenyl) methyl) benzyl) acetamide (300mg, 0.708mmol, 62% yield).LCMS m/z= 424.3[M+H]+。
Step 2:(S) -2- ((6- ((4- (acetylamino methyl) benzyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) (methyl) amino) ethyl 2- ((tertbutyloxycarbonyl) amino) -3 Methylbutanoic acid ester
To (S) -2- ((tertbutyloxycarbonyl) amino) -3 Methylbutanoic acid (128mg, 0.590mmol) in tetrahydrofuran HOBt (136mg, 0.885mmol), TEA (0.25mL, 1.77mmol) are added in solution in (15mL), N- (3- is then added Dimethylaminopropyl)-N- ethyl-carbodiimide hydrochloride (170mg, 0.885mmol).The mixture is stirred 0.5 at 25 DEG C Hour.Then N- (4- (((3,5- dicyano -4- ethyl -6- ((2- hydroxyethyl) (methyl) amino) pyridine -2- base) sulphur is added Base) methyl) benzyl) acetamide (250mg, 0.590mmol).The mixture is stirred 16 hours.The mixture is concentrated under reduced pressure. The residue is diluted with ethyl acetate (20mL) and is washed with water (10mL).The organic phase is concentrated, then by the residue It is purified with column chromatography (DCM/MeOH=50:1), obtains (S) -2- ((tertbutyloxycarbonyl) amino) -3 Methylbutanoic acid 2- ((6- ((4- (acetylamino methyl) benzyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) amino) ethyl ester (150mg, 0.241mmol, 41% yield).LCMS m/z=645.2 [M+Na]+。
Step 3:(S) -2- amino -3 Methylbutanoic acid 2- ((6- ((4- (acetylamino methyl) benzyl) sulfenyl) -3,5- two Cyano -4- ethylpyridine -2- base) (methyl) amino) ethyl ester, trifluoroacetate
At 0 DEG C, (S) -2- ((uncle is added in the mixture in methylene chloride (8mL) to TFA (1mL, 12.98mmol) Butoxy carbonyl) amino) -3 Methylbutanoic acid 2- ((6- ((4- (acetylamino methyl) benzyl) sulfenyl) -3,5- dicyano -4- ethyl Pyridine -2- base) (methyl) amino) ethyl ester (100mg, 0.161mmol).The mixture is stirred 16 hours at 25 DEG C.It should Mixture concentration, then which is washed, obtain (S) -2- amino -3 Methylbutanoic acid 2- ((6- ((4- with ethyl acetate (acetylamino methyl) benzyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) amino) ethyl ester, trifluoro second Hydrochlorate (50mg, 0.079mmol, 49% yield).LCMS m/z=523.4 [M+H]+。1H NMR (400MHz, DMSO-d6)δppm 8.36-8.44 (m, 4H), 7.36 (d, J=8Hz, 2H), 7.22 (d, J=8Hz, 2H), 4.52-4.46 (m, 3H), 4.39-4.34 (m, 1H), 4.23-4.18 (m, 3H), 4.06-4.00 (m, 1H), 3.89 (br s, 1H), 3.44 (s, 3H), 2.82-2.76 (m, 2H), 2.08-2.03 (m, 1H), 1.87 (s, 3H), 1.24-1.20 (m, 3H), 0.89-0.86 (m, 6H).
Embodiment 268
2- amino-N- (4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl) Benzyl) acetamide
Step 1:4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl) benzyl T-butyl carbamate
At -20 DEG C, to 2- (dimethylamino) -4- ethyl -6- mercaptopyridine -3,5- dimethoxy nitrile (in embodiment 92, step Synthesis, 700mg, 3.01mmol are described in rapid 3) and Et3Suspension of the N (0.420mL, 3.01mmol) in chloroform (5mL) Solution of middle addition 4- (bromomethyl) the benzylcarbamate tert-butyl ester (905mg, 3.01mmol) in chloroform (10mL).Then will The reaction mixture stirs 2 hours at -20 DEG C.Then the reaction mixture diluted with EtOAc and by the mixture water (3x) washing.Then combined water layer is stripped with EtOAc (1x).Combined organic layer is washed with brine, it is dry (MgSO4) and be concentrated.Then the thick material normal-phase chromatography is purified (Biotage Isolera, 50g SNAP ULTRA column, Hexane/EtOAc), obtain 4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl) benzyl T-butyl carbamate (1.12g), is white solid.LCMS m/z=474.3 [M+Na]+。
Step 2:2- ((4- (amino methyl) benzyl) sulfenyl) -6- (dimethylamino) -4- ethylpyridine -3,5- diformazan Nitrile dihydrochloride
By 4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl) benzylamino Suspension of the t-butyl formate (1.1g, 2.436mmol) in the solution (4M, dioxanes, 10mL, 40mmol) of HCl is in room temperature Stirring.After being stirred at room temperature 2.5 hours, then the reaction mixture is concentrated.Then resulting materials are suspended in EtOAc simultaneously Ultrasonic treatment.The solid is filtered and is washed with EtOAc, Et is then used2O washing.The solid is dry in vacuum drying oven, it obtains To 2- ((4- (amino methyl) benzyl) sulfenyl) -6- (dimethylamino) -4- ethylpyridine -3,5- dimethoxy nitrile dihydrochloride (936mg) is white solid LCMS m/z=352.3 [M+H]+。
Step 3:(2- ((4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl) Benzyl) amino) -2- oxoethyl) t-butyl carbamate
In room temperature, to solution of the Boc- glycine (35mg, 0.200mmol) in n,N-Dimethylformamide (1.0mL) Middle addition HATU (75mg, 0.198mmol).Then the reaction mixture is stirred at room temperature 15 minutes, 2- ((4- is added at this time (amino methyl) benzyl) sulfenyl) -6- (dimethylamino) -4- ethylpyridine -3,5- dimethoxy nitrile, hydrochloride (84mg, 0.217mmol) and Et3N (0.038mL, 0.270mmol).The reaction mixture is stirred at room temperature overnight.By the mixture mistake It filters and purifies (Gilson, 30mm x 50mm Gemini column, NH with reversed-phase HPLC4OH modifying agent), obtain (2- ((4- (((3, 5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl) benzyl) amino) -2- oxoethyl) amino T-butyl formate (83mg), is white solid.LCMS m/z=531.3 [M+Na]+。
Step 4:2- amino-N- (4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) Methyl) benzyl) acetamide
In room temperature, by (2- ((4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) first Base) benzyl) amino) -2- oxoethyl) t-butyl carbamate (58mg, 0.114mmol) be suspended in HCl solution (4M, two dislike Alkane, 1000 μ l, 4.0mmol).After being stirred at room temperature 2 hours, then the reaction mixture is concentrated.Resulting materials are suspended in MeOH is simultaneously free-basing with isopropylamine.The mixture reversed-phase HPLC is purified (Gilson, 30mm x 50mm Gemini column, NH4OH modifying agent), obtain 2- amino-N- (4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulphur Base) methyl) benzyl) acetamide (33mg) is pale beige solid.LCMS m/z=409.3 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.30 (t, J=5.83Hz, 1H), 7.36 (d, J=8.11Hz, 2H), 7.22 (d, J=8.36Hz, 2H), 4.50 (s, 2H), 4.27 (d, J=6.08Hz, 2H), 3.12 (s, 2H), 2.76 (q, J=7.44Hz, 2H), 1.84 (br.s., 2H), 1.21 (t, J=7.60Hz, 3H).6 protons do not measure.
Embodiment 269
4- ethyl -2- (4- methyl-1,4- Diazesuberane -1- base) -6- ((4- ((2- oxo-pyrrolidine -1- base) first Base) benzyl) sulfenyl) pyridine -3,5- dimethoxy nitrile
Step 1:1- (4- (hydroxymethyl) benzyl) pyrrolidin-2-one
At 0 DEG C, hydrogen is added in the solution in tetrahydrofuran (5mL) to pyrrolidin-2-one (0.152mL, 2.0mmol) Change sodium (60wt%, 80mg, 2.000mmol).Then the reaction mixture is stirred 30 minutes in the temperature, (4- is added at this time (bromomethyl) phenyl) methanol (402mg, 2.000mmol).Then the reaction mixture is warmed to 20 DEG C and is stirred in the temperature It is for the weekend.The reaction mixture is diluted and is washed with water with EtOAc.Water layer is stripped with EtOAc (2x).Then will merge Organic layer washed with saturated brine (1x), dry (Na2SO4) and concentration.The thick material reversed-phase HPLC is purified (Gilson, 30mm x 50mm Gemini column, NH4OH modifying agent), 1- (4- (hydroxymethyl) benzyl) pyrrolidin-2-one (83mg) is obtained, It is Tan solid.LCMS m/z=206.2 [M+H]+。
Step 2:1- (4- (chloromethyl) benzyl) pyrrolidin-2-one
In room temperature, to 1- (4- (hydroxymethyl) benzyl) pyrrolidin-2-one (80mg, 0.390mmol), DMAP (5mg, 0.041mmol) and methane sulfonyl chloride is added in the solution of DIEA (0.136mL, 0.780mmol) in methylene chloride (2.0mL) (0.030mL, 0.390mmol).Then the reaction mixture be stirred at room temperature 6 hours.The methane of additional equivalent is added Simultaneously the reaction mixture is stirred at room temperature by sulfonic acid chloride (0.030mL, 0.390mmol) and DIEA (0.136mL, 0.780mmol) Overnight.After being stirred overnight, which is diluted to DCM and used 1N HCl (2x), saturated brine (1x), is then washed It washs.Then by the dry (MgSO of organic layer4) and be concentrated, 1- (4- (chloromethyl) benzyl) pyrrolidin-2-one (87mg) is obtained, is Brown solid.LCMS m/z=224.0 [M+H]+。
Step 3:4- ethyl -2- (4- methyl-1,4- Diazesuberane -1- base) -6- ((4- ((2- oxo-pyrrolidine - 1- yl) methyl) benzyl) sulfenyl) pyridine -3,5- dimethoxy nitrile
At 20 DEG C, to 4- ethyl -2- sulfydryl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -3,5- diformazan Nitrile (synthesis, 53mg, 0.176mmol are described in embodiment 69, step 1) and 2- (dimethylamino) -4- ethyl -6- sulfydryl Solution of pyridine -3, the 5- dimethoxy nitrile (44mg, 0.189mmol) in n,N-Dimethylformamide (1.0mL) be (each comfortable difference In reaction bottle) Et is added3N (0.027mL, 0.192mmol).Then 1- (4- (chloromethyl) benzyl) is added into these solution Pyrrolidin-2-one (43mg, 0.192mmol).Then by the reaction mixture in mutually synthermal stirring 6 hours, instead by this at this time It answers mixture to warm to room temperature, filters, then purify (Gilson, 30mm Gemini column, NH with reversed-phase HPLC4OH modifying agent), Obtain 4- ethyl -2- (4- methyl-1,4- Diazesuberane -1- base) -6- ((4- ((2- oxo-pyrrolidine -1- base) methyl) benzyl Base) sulfenyl) pyridine -3,5- dimethoxy nitrile (57mg) is shallow brown oil.LCMS m/z=489.4 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.34-7.40 (m, J=8.11Hz, 2H), 7.16-7.20 (m, J=8.11Hz, 2H), 4.49 (s, 2H), 4.34 (s, 2H), 3.82-3.94 (m, 4H), 3.18-3.23 (m, 2H), 2.78 (q, J=7.60Hz, 2H), 2.60- 2.65 (m, 2H), 2.45-2.49 (m, 2H), 2.25-2.31 (m, 2H), 2.23 (s, 3H), 1.87-1.95 (m, 4H), 1.22 (t, J=7.60Hz, 3H).
Embodiment 270:
2- ((6- (4- (3- amino -2- oxo-pyrrolidine -1- base) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine - 2- yl) sulfenyl) -2- phenyl-acetamides, formates
Step 1:4- (2- ((tertbutyloxycarbonyl) amino) -4- (methylsulfany) butyrylamino) piperidines -1- benzyl formate
In room temperature, to 2- ((tertbutyloxycarbonyl) amino) -4- (methylsulfany) butyric acid (12.5g, 50.1mmol), HATU (22.88g, 60.2mmol) and DIEA (17.51mL, 100mmol) add in the solution in n,N-Dimethylformamide (100mL) Enter anhydrous 4- amino piperidine -1- benzyl formate (12.92g, 55.1mmol), continues 1 minute.The reaction mixture is stirred at 25 DEG C It mixes 15 hours.The mixture is poured into NaOH (1N, 100mL) and is extracted with ethyl acetate (200mL).Combined organic layer is used HCl (1N, 50mL) and salt water (100mL) washing.Combined organic layer is dried, filtered and is concentrated with sodium sulphate.By the remnants Object (is eluted) with silica gel chromatography with DCM/MeOH, obtains 4- (2- ((tertbutyloxycarbonyl) amino) -4- (methylsulfany) butyryl Amino) piperidines -1- benzyl formate (20g, 86% yield).LCMS m/z=466 [M+H]+。
Step 2: iodate (4- ((1- ((benzyl oxygroup) carbonyl) piperidin-4-yl) amino) -3- ((tertbutyloxycarbonyl) ammonia Base) -4- oxo butyl) dimethyl sulfonium
By 4- (2- ((tertbutyloxycarbonyl) amino) -4- (methylsulfany) butyrylamino) piperidines -1- benzyl formate (20g, 43mmol) mixture in MeI (54mL) stirs 15 hours at 25 DEG C.The reaction mixture is evaporated to dryness, iodate is obtained (4- ((1- ((benzyl oxygroup) carbonyl) piperidin-4-yl) amino) -3- ((tertbutyloxycarbonyl) amino) -4- oxo butyl) dimethyl Sulfonium (20g).LCMS m/z=480 [M]+。
Step 3:4- (3- ((tertbutyloxycarbonyl) amino) -2- oxo-pyrrolidine -1- base) piperidines -1- benzyl formate
Under 0 DEG C of nitrogen, to iodate (4- ((1- ((benzyl oxygroup) carbonyl) piperidin-4-yl) amino) -3- ((tertiary fourth oxygen Carbonyl) amino) -4- oxo butyl) dimethyl sulfonium (20g, 32.9mmol) and NaH (1.198g, 49.9mmol) be in methylene chloride Anhydrous DMF (19.3mL, 250mmol) is added dropwise in solution in (100mL), continues 1 minute.The reaction mixture is stirred at 25 DEG C It mixes 4 hours.The mixture is poured into saturated ammonium chloride (70mL) and extracts the solution methylene chloride (3x 200mL).It will close And organic layer be washed with brine, use MgSO4It dries, filters and is concentrated in vacuo.Thick material silica gel chromatography (is used DCM/MeOH elution), obtain 4- (3- ((tertbutyloxycarbonyl) amino) -2- oxo-pyrrolidine -1- base) piperidines -1- benzyl formate (12g).LCMS m/z=440 [M+Na]+。
Step 4:(2- oxo -1- (piperidin-4-yl) pyrrolidin-3-yl) t-butyl carbamate
By 4- (3- ((tertbutyloxycarbonyl) amino) -2- oxo-pyrrolidine -1- base) piperidines -1- benzyl formate (1.5g, 3.59mmol) stirred under 50 DEG C of nitrogen atmospheres with the suspension of Pd/C (5%, 191mg, 1.796mmol) in acetic acid (10mL) 15 hours.The mixture is filtered and is concentrated, yellow solid (1.0g) is obtained, is used in next step.LCMS m/z=284 [M +H]+。
Step 5:(1- (1- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) piperidin-4-yl) -2- oxo pyrroles Alkane -3- base) t-butyl carbamate
To chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- in 0 DEG C of stirred under nitrogen (in embodiment 3, step 2 Describe synthesis, 1.35g, 5.97mmol) and (2- oxo -1- (piperidin-4-yl) pyrrolidin-3-yl) t-butyl carbamate Anhydrous TEA (1.67mL, 11.94mmol) is added dropwise in (1.692g, 5.97mmol) in the solution in methylene chloride (15mL), continues 15 minutes.The reaction mixture is stirred 15 hours at 25 DEG C.The mixture is diluted with DCM (100mL) and uses organic layer 2M hydrochloric acid (50mL), water (50mL) and saturated brine (50mL) washing obtain the Huang of 1.6g with sodium sulphate drying and vacuum concentration Color solid.LCMS m/z=495 [M+Na]+。
Step 6:(1- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) -2- oxo-pyrrolidine -3- base) t-butyl carbamate
To (1- (1- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) piperidin-4-yl) -2- oxo-pyrrolidine -3- Base) thio second is added in the solution in n,N-Dimethylformamide (5mL) in t-butyl carbamate (700mg, 1.480mmol) Sour potassium (341mg, 2.96mmol).The reaction mixture is stirred 1 hour at 25 DEG C.Solid K is added2CO3(205mg, 1.48mmol) and methanesulfonic acid 2- amino -2- oxo -1- phenylethylester (synthesis is described in embodiment 3, step 5, 509mg, 2.22mmol).The reaction mixture is stirred 15 hours at 25 DEG C.The reaction mixture is quenched with water, is then divided Assigned between ethyl acetate (100mL) and 2M hydrochloric acid (100mL).Separation organic layer is simultaneously evaporated in vacuo, by the residue silica gel Chromatogram purification (is eluted) with DCM/MeOH, obtains product (200mg, 22% yield).LCMS m/z=626 [M+Na]+。
Step 7:2- ((6- (4- (3- amino -2- oxo-pyrrolidine -1- base) piperidin-1-yl) -3,5- dicyano -4- second Yl pyridines -2- base) sulfenyl) -2- phenyl-acetamides, formates
Under nitrogen at room temperature, to (1- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano - 4- ethylpyridine -2- base) piperidin-4-yl) -2- oxo-pyrrolidine -3- base) t-butyl carbamate (200mg, 0.331mmol) It is added at one time 2,2,2- trifluoroacetic acids (0.510mL, 6.63mmol) in the solution in methylene chloride (20mL), continues 1 point Clock.The reaction mixture is stirred 15 hours at 25 DEG C.The mixture is concentrated and washs the residue with ether and acetonitrile, Then it is purified with preparative-HPLC, uses Me-CN/0.5% formic acid as eluant, eluent, obtain 2- ((6- (4- (3- amino -2- oxygen For pyrrolidin-1-yl) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides, formates (6mg, 3% yield).LCMS m/z=504.1 [M+H]+。1H NMR (400MHz, MeOD) δ ppm 8.41 (bs, 1H), 7.55 (d, J=7.2Hz, 2H), 7.46-7.30 (m, 3H), 6.62 (bs, 1H), 5.53 (s, 1H), 4.82-4.77 (m, 2H), 4.24- 4.20 (m, 1H), 4.02-3.97 (m, 1H), 3.59-3.49 (m, 1H), 3.47-3.40 (m, 1H), 3.30-3.13 (m, 2H), 2.92 (q, J=7.5Hz, 2H), 2.56-2.51 (m, 1H), 1.92-1.85 (m, 5H), 1.32 (t, J=7.6Hz, 3H).
Embodiment 272
2- ((4- (amino methyl) benzyl) sulfenyl) -6- (dimethylamino) -4- ethylpyridine -3,5- dimethoxy nitrile, hydrochloric acid Salt
Step 1:4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl) benzyl T-butyl carbamate
2- (dimethylamino) -4- ethyl -6- mercaptopyridine -3,5- dimethoxy nitrile (is described in embodiment 92, step 3 Synthesis, 109mg, 0.469mmol) it is dissolved in n,N-Dimethylformamide (3mL) and the solution is cooled to 0 DEG C.Three second are added The tertiary fourth of 4- (bromomethyl) benzylcarbamate being dissolved in additional DMF (1mL) is then added dropwise in amine (0.098mL, 0.704mmol) Ester (141mg, 0.469mmol).Then the reaction is monitored by LCMS until starting material is depleted.The DMF is evaporated and incited somebody to action The thick material is dissolved in ethyl acetate and is washed with water, then dry with sodium sulphate.By material silica gel chromatography, 0-15% is used (solution of 2M the ammonium hydroxide in methyl alcohol)/chloroform of gradient elutes.It will determine that the fraction for corresponding to product merges by LCMS, then Vacuum concentration, obtains 4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl) benzyl ammonia Base t-butyl formate (159mg, 0.352mmol, 75% yield), is brown solid.LCMS m/z=452.4 [M+H]+。
Step 2:2- ((4- (amino methyl) benzyl) sulfenyl) -6- (dimethylamino) -4- ethylpyridine -3,5- diformazan Nitrile, hydrochloride
To the 4- (((3,5- dicyano -6- (dimethylamino for being dissolved in 1,4- dioxanes (4mL) and being cooled down in ice-water bath Base) -4- ethylpyridine -2- base) sulfenyl) methyl) in solution in the benzylcarbamate tert-butyl ester (143mg, 0.317mmol) plus Enter HCl (dioxane of 4M, 0.962mL, 31.7mmol).It should after the reaction is warmed to room temperature and is stirred at room temperature overnight Yellow solution gradually becomes suspension.The solid by filtration is collected and is washed with ether.By gained pale solid 55 DEG C vacuum drying, obtain 2- ((4- (amino methyl) benzyl) sulfenyl) -6- (dimethylamino) -4- ethylpyridine -3,5- diformazan Nitrile, hydrochloride (119mg, 0.307mmol, 97% yield), is pale solid.LCMS m/z=352.2 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.25 (br.s., 3H), 7.49-7.45 (m, 2H), 7.44-7.40 (m, 2H), 4.54 (s, 2H), 4.05-3.97 (m, 2H), 3.34 (s, 6H), 2.77 (q, J=7.6Hz, 2H), 1.21 (t, J=7.6Hz, 3H).
Embodiment 273
N- (4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl) phenyl) second Amide
Step 1:2- ((4- aminobenzyl) sulfenyl) -6- (dimethylamino) -4- ethylpyridine -3,5- dimethoxy nitrile
At 0 DEG C, to 2- (dimethylamino) -4- ethyl -6- mercaptopyridine -3,5- dimethoxy nitrile (in embodiment 92, step 3 In describe synthesis, 400mg, 1.722mmol) and TEA (0.480mL, 3.44mmol) be added dropwise in the solution in DCM (8mL) (4- (bromomethyl) phenyl) solution of t-butyl carbamate (493mg, 1.722mmol) in DCM (4mL).The reaction is mixed Object is closed to be stirred at room temperature overnight.The reaction mixture is concentrated and residue 20%TFA/DCM (10mL) processing 2 is small When.The reaction mixture is concentrated and uses NH4The methanol solution of OH alkalizes, be then concentrated with silica gel and use column purification (24g column), using 0-50%EtOAc/ hexane, obtain 2- ((4- aminobenzyl) sulfenyl) -6- (dimethyl Amino) -4- ethylpyridine -3,5- dimethoxy nitrile (454mg, 1.345mmol, 78% yield) is pale solid.LCMS m/z =338.2 [M+H]+.1H NMR (400MHz, DMSO-d6) ppm 1.21 (t, J=7.6Hz, 3H), 2.76 (q, J=7.6Hz, 2H), 3.36 (s, 6H), 4.35 (s, 2H), 5.12 (s, 2H), 6.50 (d, J=8.6Hz, 2H), 7.05 (d, J=8.4Hz, 2H).
Step 2:N- (4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl) benzene Base) acetamide
At 0 DEG C, to 2- ((4- aminobenzyl) sulfenyl) -6- (dimethylamino) -4- ethylpyridine -3,5- dimethoxy nitrile Chloroacetic chloride is added in the solution in THF (3mL) in (80mg, 0.237mmol) and TEA (0.083mL, 0.593mmol) (0.025mL, 0.356mmol).The reaction mixture is stirred at room temperature overnight.The reaction mixture is concentrated and uses RP- HPLC purifies (30-60% acetonitrile/water, 0.1%NH4OH is in water), obtain N- (4- (((3,5- dicyano -6- (dimethylaminos Base) -4- ethylpyridine -2- base) sulfenyl) methyl) phenyl) acetamide (55mg, 0.145mmol, 61% yield) is canescence Solid.LCMS m/z=380.2 [M+H]+.1H NMR (400MHz, DMSO-d6) δ ppm 1.21 (t, J=7.6Hz, 3H), 2.03 (s, 3H), 2.76 (q, J=7.4Hz, 2H), 4.46 (s, 2H), 7.33 (m, J=8.6Hz, 2H), 7.53 (m, J=8.6Hz, 2H), 9.97 (s, 1H).6 protons do not measure
Embodiment 274:
(2S) -2- amino -3 Methylbutanoic acid 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyan Base -4- ethylpyridine -2- base) piperidin-4-yl ester
Step 1:(2S) -2- ((tertbutyloxycarbonyl) amino) -3 Methylbutanoic acid 1- (6- ((2- amino -2- oxo -1- benzene Base ethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl ester
At 0 DEG C, to (S) -2- ((tertbutyloxycarbonyl) amino) -3 Methylbutanoic acid (153mg, 0.705mmol) and triethylamine (0.098mL, 0.705mmol) is added 2 in the solution in tetrahydrofuran (2.000mL) and n,N-Dimethylformamide (2mL), 4,6- trichloro-benzoyl chlorides (172mg, 0.705mmol) simultaneously stir the reaction mixture 3 hours mutually synthermal.Then 0 DEG C be added DMAP (86mg, 0.705mmol), then be added 2- ((3,5- dicyano -4- ethyl -6- (4- hydroxy piperidine -1- base) Pyridine -2- base) sulfenyl) -2- phenyl-acetamides (synthesis, 0.705mmol are described in embodiment 48,300mg).By the reaction Mixture stirs 3 hours at 27 DEG C.It is extracted by the reaction mixture down to cold water (50mL) and with ethyl acetate (3x 50mL). Combined organic phase is washed with saturated sodium chloride solution (50mL), with sodium sulphate drying and vacuum concentration, obtains the crude product. By raw product with silica gel chromatography (100-200 mesh is eluted with 50% hexane/EtOAc), (2S) -2- ((tertiary fourth oxygen is obtained Carbonyl) amino) -3 Methylbutanoic acid 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl Pyridine -2- base) piperidin-4-yl ester (300mg, 69% yield) is light tan solid.LCMS m/z=621.6 [M+H]+。
Step 2:(2S) -2- amino -3 Methylbutanoic acid 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3, 5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl ester
At 0 DEG C, hydrochloric acid (4M in Isosorbide-5-Nitrae-dioxanes, 2.5mL, 10.00mmol) is added into (2S) -2- ((tertiary butyloxycarbonyl Base) amino) -3 Methylbutanoic acid 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl ester (250mg, 0.392mmol) in the agitating solution in Isosorbide-5-Nitrae-dioxanes (2mL), then should Reaction mixture is stirred at room temperature 2 hours.The reaction mixture is concentrated under reduced pressure, crude product (200mg) is obtained, is shallow Brown solid.Under alkaline condition, crude compound preparative-HPLC is purified, obtains (2S) -2- amino -3- methyl Butyric acid 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidines -4- Base ester (83mg, 40% yield), is white solid.LCMS m/z=521.3 [M+H]+。1H NMR (400MHz, DMSO-d6)δ Ppm 7.90 (s, 1H), 7.67-7.47 (m, 2H), 7.43-7.16 (m, 4H), 5.53 (s, 1H), 5.08-5.01 (m, 1H), 4.09-4.01 (m, 2H), 3.88-3.76 (m, 2H), 3.13 (d, J=5.4Hz, 1H), 2.76 (q, J=7.5Hz, 2H), 2.01- 1.93 (m, 3H), 1.72-1.62 (m, 4H), 1.21 (t, J=7.6Hz, 3H), 0.90 (d, J=6.8Hz, 3H), 0.85 (d, J= 6.8Hz, 3H).
Embodiment 275:
(2S) -2- amino -3 Methylbutanoic acid 2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- two Cyano -4- ethylpyridine -2- base) (methyl) amino) ethyl ester
Step 1:(2S) -2- ((tertbutyloxycarbonyl) amino) -3 Methylbutanoic acid 2- ((6- ((2- amino -2- oxo -1- benzene Base ethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) amino) ethyl ester
At 0 DEG C, to (S) -2- ((tertbutyloxycarbonyl) amino) -3 Methylbutanoic acid (149mg, 0.688mmol) and triethylamine (0.096mL, 0.688mmol) is added 2 in the solution in tetrahydrofuran (2.000mL) and n,N-Dimethylformamide (2mL), 4,6- trichloro-benzoyl chlorides (168mg, 0.688mmol) simultaneously stir the reaction mixture 1 hour mutually synthermal.Then 0 DEG C be added DMAP (84mg, 0.688mmol), then be added 2- ((3,5- dicyano -4- ethyl -6- ((2- hydroxyethyl) (first Base) amino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides (describe synthesis in embodiment 147, step 2,300mg, 0.688mmol).The reaction mixture is stirred 2 hours at 27 DEG C.The reaction mixture down to ice cold water (50mL) and is used into second Acetoacetic ester (3x 50mL) extraction.Combined organic layer is washed with saturated sodium chloride solution (50mL), it is dry and true with sodium sulphate Sky evaporation, obtains the crude product.By raw product with silica gel column purification (100-200 mesh is eluted with 50% hexane/EtOAc), obtain To (2S) -2- ((tertbutyloxycarbonyl) amino) -3 Methylbutanoic acid 2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) - 3,5- dicyano -4- ethylpyridine -2- bases) (methyl) amino) ethyl ester (260mg, 59% yield) is light tan solid. LCMS m/z=595.3 [M+H]+。
Step 2:(2S) -2- amino -3 Methylbutanoic acid 2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) - 3,5- dicyano -4- ethylpyridine -2- base) (methyl) amino) ethyl ester
At 0 DEG C, hydrochloric acid (4M in Isosorbide-5-Nitrae-dioxanes, 2.5mL, 10.00mmol) is added into (2S) -2- ((tertiary butyloxycarbonyl Base) amino) -3 Methylbutanoic acid 2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) (methyl) amino) ethyl ester (260mg, 0.437mmol) in the agitating solution in Isosorbide-5-Nitrae-dioxanes (5mL) and will The reaction mixture is stirred at room temperature 2 hours.The reaction mixture is concentrated under reduced pressure, light tan solid is obtained.This is thick Produced compounds use preparative-HPLC to purify under alkaline condition, obtain (2S) -2- amino -3- ethyl butyric acid 2- ((6- ((2- ammonia Base -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) amino) ethyl ester (85mg, 38% yield), it is white solid.LCMS m/z=495.3 [M+H]+。1H NMR (400MHz, DMSO-d6)δppm 7.90 (br s, 1H), 7.50 (d, J=8.33Hz, 2H), 7.41-7.29 (m, 4H), 5.53 (d, J=3.07Hz, 1H), 4.33-3.99 (m, 4H), 3.39 (d, J=1.97Hz, 3H), 3.05 (dd, J=11.40,5.26Hz, 1H), 2.77 (q, J=7.60Hz, 2H), 1.74-1.55 (m, 3H), 1.20 (t, J=7.45Hz, 3H), 0.66-0.85 (m, 6H).
Embodiment 276:
2,2'- ((3,5- dicyano -4- ethylpyridine -2,6- diyl) bis- (sulfane diyls)) bis- (2- phenyl-acetamides)
Step 1:2- sulfydryl -2- phenyl-acetamides
To thioacetic acid S- (2- amino -2- oxo -1- phenylethyl) ester stirred at 0 DEG C (in embodiment 62, step 5 In describe synthesis, 502mg, 2.4mmol) be added at one time in the suspension in methanol (20mL) sodium ethoxide (164mg, 2.4mmol).The reaction mixture is stirred 2 hours at 0 DEG C.The reaction mixture is concentrated, crude 2- sulfydryl -2- is obtained Phenyl-acetamides (400mg), are employed without purifying.LCMS m/z=168.1 [M+H]+。
Step 2:2,2'- ((3,5- dicyano -4- ethylpyridine -2,6- diyl) bis- (sulfane diyls)) bis- (2- phenyl second Amide)
To the chloro- 4- ethylpyridine -3,5- dimethoxy nitrile of 2,6- bis- stirred in air at room temperature (in 3 step 2 of embodiment Describe synthesis, 226mg, 1.00mmol) and triethylamine (0.56mL, 4.00mmol) in n,N-Dimethylformamide (15mL) Solution in be added 2- sulfydryl -2- phenyl-acetamides (401mg, 2.40mmol).The reaction mixture is small in 25 DEG C of stirrings 12 When.The reaction mixture is concentrated and by the residue flash column chromatography, obtains 2,2'- ((3,5- dicyano -4- second Yl pyridines -2,6- diyl) bis- (sulfane diyls)) bis- (2- phenyl-acetamides) (135mg, 27%), it is light yellow solid.LCMS M/z=487.9 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.06 (br s, 2H), 7.78 (br s, 2H), 7.53- 7.49 (m, 4H), 7.48-7.39 (m, 6H), 5.81 (s, 2H), 2.83 (q, J=7.6Hz, 2H), 1.23 (t, J=7.6Hz, 3H)。
Embodiment 277
(2S) -2- amino -3 Methylbutanoic acid (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- two Cyano-4-ethylpyridine-2- base) azetidine-3- base) methyl ester tfa salt
Step 1:(2S) -2- ((tertbutyloxycarbonyl) amino) -3 Methylbutanoic acid (1- (6- ((2- amino -2- oxo -1- benzene Base ethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) azetidine -3- base) methyl ester
To 2- ((3,5- dicyano -4- ethyl -6- (3- (hydroxymethyl) azetidine -1- base) pyridine -2- base) sulphur Base) (S)-2- ((tertiary fourth oxygen is added in-2-phenyl-acetamides (150mg, 0.368mmol) in the solution in methylene chloride (20mL) Carbonyl) amino) -3 Methylbutanoic acid (160mg, 0.736mmol), HOBT (113mg, 0.736mmol), EDC (353mg, 1.841mmol) and TEA (0.257mL, 1.841mmol).The reaction mixture is stirred 5 hours.By the reaction mixture salt Water (2x20mL) washs and organic layer is concentrated under reduced pressure.The thick material residue (is washed with silica gel chromatography with DCM/MeOH It is de-), obtain (2S)-(1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) azetidine -3- base) methyl 2- ((tertbutyloxycarbonyl) amino) -3 Methylbutanoic acid ester (200mg).LCMS m/z= 607.1[M+H]+。
Step 2:(2S) -2- amino -3 Methylbutanoic acid (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) - 3,5- dicyano-4-ethylpyridine-2- base) azetidine-3- base) methyl ester tfa salt
By (2S) -2- ((tertbutyloxycarbonyl) amino) -3 Methylbutanoic acid (1- (6- ((2- amino -2- oxo -1- phenyl second Base) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) azetidine -3- base) methyl ester (200mg, 0.330mmol) plus To TFA (2mL, 26mmol) in the solution in methylene chloride (10mL).The reaction mixture is stirred 5 hours.By the mixing Object is diluted with methylene chloride (30mL) and is washed with salt water (2x 20mL).Organic layer is concentrated under reduced pressure.By thick material remnants Object (is eluted) with silica gel chromatography with DCM/MeOH, obtains (2S) -2- amino -3 Methylbutanoic acid (1- (6- ((2- amino -2- Oxo-1- phenylethyl) sulfenyl)-3,5- dicyano-4-ethylpyridine-2- base) azetidine-3- base) methyl ester tfa salt (150mg).LCMS m/z=507.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.47 (s, 3H), 7.94 (s, 1H), 7.53 (d, J=7.2Hz, 2H), 7.43-7.23 (m, 4H), 5.60 (s, 0.5H), 5.58 (s, 0.5H), 4.68-4.06 (m, 6H), 3.97 (s, 1H), 3.19-3.06 (m, 1H), 2.70 (q, J=7.4Hz, 2H), 2.21-2.07 (m, 1H), 1.18 (t, J=7.5Hz, 3H), 1.03-0.84 (m, 6H).
Embodiment 278
N- (4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl) benzyl) -2- Hydroxyl acetamide
In room temperature, to solution of the 2- hydroxyacetic acid (10mg, 0.131mmol) in n,N-Dimethylformamide (1.0mL) Middle addition HATU (49.0mg, 0.129mmol).Then the reaction mixture is stirred 30 minutes at 20 DEG C, 2- is added at this time ((4- (amino methyl) benzyl) sulfenyl) -6- (dimethylamino) -4- ethylpyridine -3,5- dimethoxy nitrile, hydrochloride is (in embodiment 272, synthesis, 50mg, 0.129mmol are described in step 2) and Et3N (0.042mL, 0.304mmol).Then the reaction is mixed It is for the weekend to close object 20 DEG C of stirrings indoors, then warms to room temperature.The mixture is filtered and is purified with reversed-phase HPLC (Gilson, 30mm x 50mm Gemini column, NH4OH modifying agent), obtain N- (4- (((3,5- dicyano -6- (dimethylaminos Base) -4- ethylpyridine -2- base) sulfenyl) methyl) benzyl) -2- hydroxyl acetamide (36mg) is pale solid.LCMS m/ Z=410.4 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.29 (d, J=6.08Hz, 1H), 7.36 (t, J= 7.10Hz, 2H), 7.23 (d, J=7.60Hz, 2H), 5.51 (br.s., 1H), 4.50 (d, J=6.59Hz, 2H), 4.23-4.32 (m, 2H), 3.85 (br.s., 2H), 3.36 (br.s., 6H), 2.72-2.80 (m, 2H), 1.18-1.25 (m, 3H).
Embodiment 279
3- amino-N- (4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl) Benzyl) propionamide
Step 1:(3- ((4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl) Benzyl) amino) -3- oxopropyl) t-butyl carbamate
At 20 DEG C, to 3- ((tertbutyloxycarbonyl) amino) propionic acid (27mg, 0.143mmol)) in n,N-Dimethylformamide HATU (54mg, 0.142mmol) is added in solution in (1.0mL).Then the reaction mixture is stirred 30 minutes at 20 DEG C, 2- ((4- (amino methyl) benzyl) sulfenyl) -6- (dimethylamino) -4- ethylpyridine -3,5- dimethoxy nitrile, hydrochloric acid are added at this time Salt (describes synthesis, 50mg, 0.129mmol) in embodiment 272, step 2, and Et is then added3N (0.036mL, 0.258mmol).Then the reaction mixture is stirred 3.5 hours at 20 DEG C.The reaction is warmed to room temperature.Then this is anti- It answers mixture to filter and purifies (Gilson, 30mm x 50mm Gemini column, NH with reversed-phase HPLC4OH modifying agent), obtain (3- ((4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl) benzyl) amino) -3- oxo Propyl) t-butyl carbamate (52mg) is white solid.LCMS m/z=545.4 [M+Na]+。
Step 2:3- amino-N- (4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) Methyl) benzyl) propionamide
In room temperature, by (3- ((4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) first Base) benzyl) amino) -3- oxopropyl) t-butyl carbamate (34mg, 0.065mmol)) and be suspended in 4M HCl (1500 μ l, 6.0mmol) the solution in dioxanes.The reaction mixture is stirred at room temperature 2 hours, it is then that the reaction mixture is dense Contracting.By the residue be suspended in MeOH and with isopropylamine it is free-basing.The mixture reversed-phase HPLC is purified (Gilson, 30mm x 50mm Gemini column, NH4OH modifying agent), obtain 3- amino-N- (4- (((3,5- dicyano -6- (dimethylaminos Base) -4- ethylpyridine -2- base) sulfenyl) methyl) benzyl) propionamide (23mg) is white solid.LCMS m/z=423.4 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.40 (t, J=5.83Hz, 1H), 7.36 (d, J=8.11Hz, 2H), 7.21 (d, J=8.36Hz, 2H), 4.50 (s, 2H), 4.24 (d, J=5.83Hz, 2H), 2.72-2.81 (m, 4H), 2.21 (t, J =6.59Hz, 2H), 1.43 (br.s., 2H), 1.21 (t, J=7.60Hz, 3H).6 protons do not measure.
Embodiment 281:
2- ((6- (3- aminoazetidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide:
Step 1:(1- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) azetidine -3- base) carbamic acid uncle Butyl ester
At 0 DEG C, to azetidine -3- carbamate (1.587g, 9.22mmol) in methylene chloride Triethylamine (3.50mL, 25.1mmol) and 2 is added in solution in (25mL), chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 6- bis- (describing synthesis, 2g, 8.38mmol in 3 step 2 of embodiment).The reaction mixture is stirred 2 hours at 27 DEG C.This is anti- Mixture is answered to be quenched with ice cold water (250mL) and extracted with DCM (3x 250mL).Combined organic layer is washed with water (250mL) It washs, uses Na2SO4It dries, filters and is concentrated in vacuo, obtain (1- (chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-) azacyclo- Butane -3- base) t-butyl carbamate (2.4g) is pale solid.LCMS m/z=362.5 [M+H]+。
Step 2:(1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) azetidine -3- base) t-butyl carbamate
In room temperature, to (1- (chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-) azetidine -3- base) amino first Thioacetic acid potassium is added in the solution in n,N-Dimethylformamide (20mL) in tert-butyl acrylate (2.4g, 5.89mmol) (1.344g, 11.77mmol) and the reaction mixture is stirred 2 hours mutually synthermal.0 DEG C of addition potassium carbonate (1.627g, 11.77mmol), methanesulfonic acid 2- amino -2- oxo -1- phenylethylester is then added and (describes conjunction in 3 step 5 of embodiment At 2.072g, 8.83mmol).The reaction mixture is stirred at room temperature 16 hours.By the reaction mixture down to ice cold water It (250mL) and is extracted with ethyl acetate (3x 250mL).By combined organic layer water (200mL) and saturated brine solution (200mL) washing, is dried, filtered and is concentrated in vacuo with sodium sulphate.By the residue with positive the penta of DCM (1mL) and 10%EtOAc Alkane solution (2x 30mL) grinding.Obtained solid is further purified with silica gel chromatograph to (100-200 mesh, the DCM with 3% methanol are molten Liquid elution), obtain (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) azetidine -3- base) t-butyl carbamate (1g, 72% yield) is pale solid.LCMS m/z=493.2 [M+H]+。
Step 3:2- ((6- (3- aminoazetidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides
At 0 DEG C, solution of the TFA (0.513mL, 3.33mmol) in methylene chloride (5mL) is added into (1- (6- ((2- ammonia Base -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) azetidine -3- base) amino first Tert-butyl acrylate (700mg, 1.331mmol) is in the agitating solution in methylene chloride (5mL).The reaction mixture is stirred in room temperature It mixes 2 hours.The reaction mixture is concentrated under reduced pressure, the light tan solid of 700mg is obtained.It prepared by the 400mg material Type-HPLC purifying, obtains 2- ((6- (3- aminoazetidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides (140mg) are pale solid.LCMS m/z=393.1 [M+H]+。1H NMR (400MHz, DMSO- D6) δ ppm 7.87 (s, 1H), 7.62-7.46 (m, 2H), 7.46-7.17 (m, 4H), 5.55 (s, 1H), 4.63-4.48 (m, 2H), 4.08-3.81 (m, 3H), 2.68 (q, J=7.4Hz, 2H), 2.22 (bs, 2H), 1.17 (t, J=7.6Hz, 3H).
Embodiment 282
(S) -2- amino -3 Methylbutanoic acid 1- (6- ((4- (acetylamino methyl) benzyl) sulfenyl) -3,5- dicyano -4- Ethylpyridine -2- base) azetidine -3- base ester, trifluoroacetate
The chloro- 4- ethyl -6- of step 1:2- (3- hydroxy azetidine -1- base) pyridine -3,5- dimethoxy nitrile
By chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile (1g, 4.42mmol) of 2,6- bis-, aza-cyclobutane -3-alcohol (0.323g, 4.42mmol) and triethylamine (0.448g, 4.42mmol) add to methylene chloride (100mL).By the mixture 25 DEG C stirring 2 hours.The solvent in vacuo is evaporated.Remaining residue is allocated between DCM (100mL) and water (50mL).Point From each layer and organic layer is washed with brine, is dried and concentrated.By the thick residue silica gel chromatography, the chloro- 4- of 2- is obtained Ethyl -6- (3- hydroxy azetidine -1- base) pyridine -3,5- dimethoxy nitrile (900mg), is white solid.LCMS m/z= 263[M+H]+。
Step 2:N- (4- (((3,5- dicyano -4- ethyl -6- (3- hydroxy azetidine -1- base) pyridine -2- base) Sulfenyl) methyl) benzyl) acetamide
By the chloro- 4- ethyl -6- of 2- (3- hydroxy azetidine -1- base) pyridine -3,5- dimethoxy nitrile (850mg, 3.24mmol) n,N-Dimethylformamide (50mL) is added to thioacetic acid potassium (739mg, 6.47mmol)).The mixture is stirred After mixing 2 hours, N- (4- (bromomethyl) benzyl) acetamide (1175mg, 4.85mmol) is added.The mixture is stirred 15 hours, The solvent in vacuo is evaporated, remaining residue is allocated between DCM (40mL) and water (20mL).Organic layer is separated, salt is used Water washing dries and concentrates.By the thick residue with silica gel chromatography (ethyl acetate: petroleum ether=1:2), N- (4- is obtained (((3,5- dicyano -4- ethyl -6- (3- hydroxy azetidine -1- base) pyridine -2- base) sulfenyl) methyl) benzyl) acetamide (500mg) is white solid.LCMS m/z=422.1 [M+H]+。
Step 3:(S) -2- ((tertbutyloxycarbonyl) amino) -3 Methylbutanoic acid 1- (6- ((4- (acetylamino methyl) benzyl Base) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) azetidine -3- base ester
By N- (4- (((3,5- dicyano -4- ethyl -6- (3- hydroxy azetidine -1- base) pyridine -2- base) sulfenyl) Methyl) benzyl) acetamide (180mg, 0.427mmol), (S) -2- ((tertbutyloxycarbonyl) amino) -3 Methylbutanoic acid (93mg, 0.427mmol)、N1((ethylimino) methylene)-N3,N3Dimethyl propylene -1,3- diamines (265mg, 1.708mmol), HOBt (229mg, 1.495mmol) and triethylamine (173mg, 1.708mmol) add to methylene chloride (50mL).The mixture is existed 25 DEG C are stirred 15 hours.Water (50mL) is added into the mixture.Organic layer is separated, is washed with brine, is dried and concentrated.This is thick Residue obtains (S) -2- ((tertbutyloxycarbonyl) amino) -3- first with silica gel chromatography (ethyl acetate: petroleum ether=1:5) Base butyric acid 1- (6- ((4- (acetylamino methyl) benzyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) azetidin Alkane -3- base ester (350mg), is faint yellow solid.LCMS m/z=643.2 [M+Na]+。
Step 4:(S) -2- amino -3 Methylbutanoic acid 1- (6- ((4- (acetylamino methyl) benzyl) sulfenyl) -3,5- two Cyano -4- ethylpyridine -2- base) azetidine -3- base ester, trifluoroacetate
By (S) -2- ((tertbutyloxycarbonyl) amino) -3 Methylbutanoic acid 1- (6- ((4- (acetylamino methyl) benzyl) sulphur Base) -3,5- dicyano -4- ethylpyridine -2- base) azetidine -3- base ester (350mg, 0.564mmol) adds to methylene chloride (20mL) then 2,2,2- trifluoroacetic acids (129mg, 1.128mmol) are added at 0 DEG C.The mixture is stirred 15 at 25 DEG C Hour.The solvent is removed and purifies remaining residue preparative-HPLC, obtains (S) -2- amino -3 Methylbutanoic acid 1- (6- ((4- (acetylamino methyl) benzyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) azetidine -3- base Ester, trifluoroacetate (100mg), is white solid.LCMS m/z=521.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.52 (s, 3H), 8.36 (t, J=5.8Hz, 1H), 7.36 (d, J=8.0Hz, 2H), 7.20 (d, J=8.0Hz, 2H), 5.42 (ddd, J=10.4,6.9,3.8Hz, 1H), 4.84 (s, 2H), 4.48 (s, 2H), 4.42 (s, 2H), 4.22 (d, J= 5.9Hz, 2H), 4.01 (s, 1H), 2.72 (q, J=7.7Hz, 2H), 2.24 (dd, J=11.9,6.8Hz, 1H), 1.87 (s, 3H), 1.20 (t, J=7.6Hz, 3H), 1.04 (d, J=6.9Hz, 3H), 1.00 (d, J=6.9Hz, 3H).
Embodiment 283:
2- ((3,5- dicyano -4- ethyl -6- picoline -2- base) sulfenyl) -2- phenyl-acetamides
The chloro- 4- ethyl -6- picoline -3,5- dimethoxy nitrile of step 1:2-
At 0 DEG C, NBS (3.51g, 19.73mmol) is added into 4- ethyl -6- methyl -2- oxo -1,2- dihydropyridine -3- Formonitrile HCN (1.6g, 9.87mmol) is in H2SO4In agitating solution in (5mL, 94mmol) and trifluoroacetic acid (5mL, 64.9mmol). The mixture is stirred 15 hours at 0 DEG C.Then it is filtered down in ice water and by the solid, obtains crude material.It should The mixture of roughage (1.2g) and copper cyanider (535mg, 5.97mmol) in n-methyl-2-pyrrolidone (40mL) is 200 It is stirred 48 hours under DEG C nitrogen atmosphere.It is then cooled to room temperature and is extracted with ethyl acetate and water, organic layer in vacuo is concentrated Purified to dry doubling with column chromatography, obtains crude product.By the crude product (320mg) and POCl3The mixture of (20ml, 215mmol) It is stirred 18 hours in 150 DEG C of seal pipes.After reaction cooling, which is concentrated in vacuo, obtains crude product simultaneously It is further purified with column chromatography, obtains chloro- 4- ethyl -6- picoline -3, the 5- dimethoxy nitrile (289mg, 1.41mmol) of 2- 。1H NMR (400MHz, CDCl3) δ 3.08 (q, J=7.7Hz, 2H), 2.82 (s, 3H), 1.38 (t, J=7.7Hz, 3H).
Step 2:2- ((3,5- dicyano -4- ethyl -6- picoline -2- base) sulfenyl) -2- phenyl-acetamides
By chloro- 4- ethyl -6- picoline -3, the 5- dimethoxy nitrile (110mg, 0.54mmol) of 2- and thioacetic acid potassium The mixture of (64.1mg, 0.56mmol) in DMF (10mL) stirs 1 hour at 20 DEG C.Then the bromo- 2- phenylacetyl of 2- is added The mixture is simultaneously stirred for 13 hours by amine (229mg, 1.07mmol) and triethylamine (0.224mL, 1.61mmol).Then by it It is washed with water and is extracted with ethyl acetate, organic layer is dried, filtered and is concentrated in vacuo to is dry.The residue column chromatography is pure Change, obtain 2- ((3,5- dicyano -4- ethyl -6- picoline -2- base) sulfenyl) -2- phenyl-acetamides (90mg, 50.0%), It is white solid.LCMS m/z=337.2 [M+H]+。1H NMR (400MHz, CDCl3) δ ppm 7.50 (m, 2H), 7.38 (m, 3H), 6.08 (s, 1H), 5.72 (s, 1H), 5.65 (s, 1H), 2.98 (s, 2H), 2.78 (s, 3H), 1.34 (s, 3H).
Embodiment 284:
N- (4- (((3,5- dicyano -4- ethyl -6- picoline -2- base) sulfenyl) methyl) benzyl) acetamide
By chloro- 4- ethyl -6- picoline -3, the 5- dimethoxy nitrile of 2- (in 283 step 1 of embodiment describe synthesis, 110mg, 0.54mmol) and mixture of the thioacetic acid potassium (64.1mg, 0.56mmol) in DMF (10mL) at 20 DEG C stir 1 Hour.Then be added N- (4- (bromomethyl) benzyl) acetamide (259mg, 1.07mmol) and triethylamine (0.224mL, 1.61mmol) and by the mixture it is stirred for 13 hours.Then it is washed with water and is extracted with ethyl acetate and by organic layer It dries, filters and is concentrated.The residue is purified with column chromatography, obtains N- (4- (((3,5- dicyano -4- ethyl -6- methyl pyrroles Pyridine -2- base) sulfenyl) methyl) benzyl) acetamide (110mg, 56%) is white solid.LCMS m/z=365.1 [M+H]+。1H NMR (400MHz, CDCl3) δ ppm 7.37 (d, J=7.7Hz, 2H), 7.24 (d, J=7.8Hz, 2H), 5.76 (s, 1H), 4.49 (s, 2H), 4.41 (d, J=5.1Hz, 2H), 3.01-2.91 (m, 2H), 2.79 (s, 3H), 2.03 (s, 3H), 1.33 (t, J =7.6Hz, 3H).
Embodiment 285:
2- (4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl) -1H- pyrrole Azoles -1- base) acetamide
Step 1:2- (4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl) - 1H- pyrazol-1-yl) methyl acetate
In room temperature, to 2- (4- (hydroxymethyl) -1H- pyrazol-1-yl) methyl acetate (1.7g, 9.99mmol) in dichloro Be added in solution in methane (35mL) triethylamine (2.78mL, 19.98mmol) and mesyl chloride (1.168mL, 14.99mmol).By the reaction mixture in mutually synthermal stirring 20 minutes.The volatile matter is distilled in room temperature, is obtained crude Product is used in next step without purification.To 2- chloro- 6- (dimethylamino) -4- ethylpyridine -3,5- dimethoxy nitrile ( Synthesis, 1.7g, 7.24mmol are described in 3 step 3 of embodiment) it is added in the solution in n,N-Dimethylformamide (34mL) Simultaneously the reaction mixture is stirred at room temperature 2 hours for thioacetic acid potassium (1.655g, 14.49mmol).After 2 hours, by the reaction Mixture is cooled to 0 DEG C, and potassium carbonate (2.002g, 14.49mmol) then is added, and 2- (4- (((methyl sulphur then is added in room temperature Acyl group) oxygroup) methyl) -1H- pyrazol-1-yl) solution of the methyl acetate (2.338g, 9.42mmol) in DMF and by the reaction Mixture is stirred at room temperature 1 hour.The reaction mixture is diluted with water (100mL) and is extracted with ethyl acetate (200mL).It will Organic layer anhydrous Na2SO4It dries, filters and evaporates the filtrate decompression, obtain 2- (4- (((3,5- dicyano -6- (dimethyl Amino) -4- ethylpyridine -2- base) sulfenyl) methyl) -1H- pyrazol-1-yl) methyl acetate (1.9g).LCMS (m/z)=385.3 [M+H]+。
Step 2:2- (4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl) - 1H- pyrazol-1-yl) acetic acid
In room temperature, to 2- (4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) first Base) -1H- pyrazol-1-yl) methyl acetate (800mg, 2.081mmol) is in methanol (8mL), water (4mL) and tetrahydrofuran (8mL) In solution in be added and LiOH (249mg, 10.40mmol) and the reaction mixture be stirred at room temperature 1 hour.By the mixture It is diluted with water (10mL) and is acidified with dilute HCl.By obtained solid filtering and drying, 2- (4- (((3,5- dicyano -6- (two are obtained Methylamino) -4- ethylpyridine -2- base) sulfenyl) methyl) -1H- pyrazol-1-yl) acetic acid (670mg).LCMS m/z=371.2 [M+H]+。
Step 3:2- (4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl) - 1H- pyrazol-1-yl) acetamide
In room temperature, ammonium chloride (234mg, 4.38mmol) is added into 2- (4- (((3,5- dicyano -6- (dimethylaminos Base) -4- ethylpyridine -2- base) sulfenyl) methyl) -1H- pyrazol-1-yl) acetic acid (330mg, 0.877mmol), HATU (500mg, 1.315mmol) and the agitating solution of diisopropylethylamine (0.766mL, 4.38mmol) in n,N-Dimethylformamide (6mL) In, then the reaction mixture is stirred at room temperature 2 hours.The reaction mixture is diluted with ice cold water (60mL) and by gained Solid by filtration is collected.Solid is dissolved in acetonitrile (30mL) and is heated 15 minutes with charcoal (1g) at 50 DEG C.Then this is mixed Object is closed to pass throughIt filters and the filtrate is concentrated and is dried, obtain 2- (4- (((3,5- dicyano -6- (dimethylaminos Base) -4- ethylpyridine -2- base) sulfenyl) methyl) -1H- pyrazol-1-yl) acetamide (260mg, 79% yield) is canescence Solid.LCMS (m/z)=370.0 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.69 (s, 1H), 7.47-7.37 (m, 2H), 7.22 (br s, 1H), 4.70 (s, 2H), 4.36 (s, 2H), 3.36 (s, 6H), 2.77 (q, J=7.60Hz, 2H), 1.21 (t, J=7.56Hz, 3H).
Embodiment 286:
N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) Piperidin-4-yl) -2- hydroxyl acetamide
Step 1:(1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) piperidin-4-yl) t-butyl carbamate
In room temperature, to (1- (chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-) piperidin-4-yl) the tertiary fourth of carbamic acid Ester (describing synthesis, 900mg, 1.800mmol in 81 step 1 of embodiment) stirring in n,N-Dimethylformamide (10mL) It mixes and thioacetic acid potassium (411mg, 3.60mmol) is added in solution and by the reaction mixture in mutually synthermal stirring 2 hours.So Potassium carbonate (373mg, 2.70mmol) is added afterwards, methanesulfonic acid 2- amino -2- oxo -1- phenylethylester then is added in room temperature (describing synthesis, 534mg, 2.160mmol in 3 step 5 of embodiment).The reaction mixture is stirred at room temperature 16 hours, Then it is quenched in cold water (50mL) and is extracted with ethyl acetate (2x 100mL).By combined organic layer Na2SO4It is dry, mistake Filter is concentrated and is purified with column chromatography, using silica gel (100-200 mesh, with the hexanes of ethyl acetate), obtains (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl) amino first Tert-butyl acrylate (700mg).LCMS m/z=519.0 [M-H]-。
Step 2:2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide hydrochloride
At 0 DEG C, to (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) stirring of the t-butyl carbamate (700mg, 0.936mmol) in Isosorbide-5-Nitrae-dioxanes (10mL) be molten HCl (solution of the 4M in Isosorbide-5-Nitrae dioxanes, 3mL, 12.00mmol) is added in liquid, it is small which is stirred at room temperature 4 When.The reaction mixture is concentrated and ether (30mL) is used to grind, obtains 2- ((6- (4- amino piperidine -1- base) -3,5- dicyan Base -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl amine hydrochlorate (450mg, 90% yield) is brown solid.LCMS M/z=421.1 [M+H]+。
Step 3: acetic acid 2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- second Yl pyridines -2- base) piperidin-4-yl) amino) -2- oxoethyl ester
At 0 DEG C, to 2- acetoxy acid (100mg, 0.845mmol) in n,N-Dimethylformamide (10mL) DIPEA (0.295mL, 1.690mmol) and HATU (643mg, 1.690mmol) are added in agitating solution and the solution is stirred 10 Minute.After ten minutes, 2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulphur is added in room temperature Base) -2- phenylacetyl amine hydrochlorate (450mg, 0.845mmol) and the reaction mixture is stirred at room temperature 3 hours.This is anti- It answers mixture to be concentrated under reduced pressure, diluted with water (30mL) and is extracted with ethyl acetate (2x80mL).Combined organic layer is used Anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure.The residue is purified with column chromatography, uses silica gel (100-200 mesh, with 50% The hexanes of ethyl acetate), obtain acetic acid 2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3, 5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl) amino) -2- oxoethyl ester (350mg) is brown solid.LCMS M/z=521.2 [M+H]+。
Step 4:N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) -2- hydroxyl acetamide
In room temperature, to acetic acid 2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- Ethylpyridine -2- base) piperidin-4-yl) amino) -2- oxoethyl ester (350mg, 0.555mmol)) in tetrahydrofuran (5mL) Water (2.5mL) is added in agitating solution, lithium hydroxide monohydrate (23.28mg, 0.555mmol) then is added.The reaction is mixed Object is closed to be stirred at room temperature 30 minutes.The reaction mixture is quenched with cold water (20mL) and is extracted with ethyl acetate (2x 80mL). By combined organic layer Na2SO4It dries, filters and is concentrated under reduced pressure.The crude material is washed with DCM (15mL), stirs 10 points Then clock is filtered and is dried under reduced pressure, obtain N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyan Base -4- ethylpyridine -2- base) piperidin-4-yl) -2- hydroxyl acetamide (145mg, 52% yield) is pale solid. LCMS m/z=479.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.91 (s, 1H), 7.68 (d, J=8.11Hz, 1H), 7.55-7.46 (m, 2H), 7.41-7.27 (m, 4H), 5.53 (s, 1H), 5.45-5.36 (m, 1H), 4.51 (t, J= 11.62Hz, 2H), 4.05-3.94 (m, 1H), 3.81 (d, J=5.70Hz, 2H), 3.30-3.23 (m, 2H), 2.76 (q, J= 7.53Hz, 2H), 1.91-1.80 (m, 2H), 1.69-1.50 (m, 2H), 1.27-1.17 (m, 3H).
Embodiment 287
N- (4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl) phenyl) first Base sulfonamide
At 0 DEG C, to 2- ((4- aminobenzyl) sulfenyl) -6- (dimethylamino) -4- ethylpyridine -3,5- dimethoxy nitrile ( Embodiment 273 describes synthesis, 73mg, 0.216mmol in step 1) and TEA (0.075mL, 0.541mmol) at THF (3mL) In solution in methane sulfonyl chloride (0.025mL, 0.325mmol) solution in THF (0.5mL) is added dropwise.The reaction is mixed Object is stirred at room temperature 30 minutes.The reaction mixture is concentrated and purified with RP-HPLC (30-60% acetonitrile/water, 0.1% NH4OH is in water), obtain N- (4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl) Phenyl) methylsulfonamides (49mg, 0.118mmol, 55% yield) are pale solid.LCMS m/z=416.3 [M+H ]+.1H NMR (400MHz, DMSO-d6) δ ppm 1.21 (t, J=7.6Hz, 3H), 2.76 (q, J=7.4Hz, 2H), 2.96 (s, 3H), 3.34 (s, 6H), 4.47 (s, 2H), 7.12-7.17 (m, 2H), 7.36 (d, J=8.6Hz, 2H).1 proton does not measure
Embodiment 288:
N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) Azetidine -3- base) -2- hydroxyl acetamide
Step 1: acetic acid 2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- second Yl pyridines -2- base) azetidine -3- base) amino) -2- oxoethyl ester
At 0 DEG C, the stirring in n,N-Dimethylformamide (5mL) to 2- acetoxy acid (210mg, 1.782mmol) HATU (678mg, 1.782mmol) is added in solution.After ten minutes, at 0 DEG C, 2- ((6- (3- aminoazetidine -1- is added Base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides (describe conjunction in 281 step 3 of embodiment At 350mg, 0.891mmol), DIPEA (0.623mL, 3.56mmol) then is added.Then by the reaction mixture in room temperature Stirring 2 hours.The reaction mixture is extracted down in ice cold water (30mL) and with ethyl acetate (3x 30mL).By merging Organic layer is washed with saturated brine solution, uses Na2SO4It dries, filters and is concentrated.The residue is ground with ether (2x 15mL) And it is dry, obtain acetic acid 2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) azetidine -3- base) amino) -2- oxoethyl ester (400mg) is light tan solid.LCMS m/z= 493.3[M+H]+。
Step 2:N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) azetidine -3- base) -2- hydroxyl acetamide
To 0 DEG C of stirred under nitrogen acetic acid 2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3, 5- dicyano -4- ethylpyridine -2- base) azetidine -3- base) amino) -2- oxoethyl ester (350mg, 0.580mmol) exists The solution of LiOH (27.8mg, 1.161mmol) in water (2mL) is added dropwise in solution in tetrahydrofuran (2mL), continues 5 minutes. Then the reaction mixture is stirred 30 minutes at 0 DEG C.The reaction mixture down to ice cold water (10mL) and is used into ethyl acetate (3x 25mL) extraction.Combined organic layer is washed with saturated brine (25mL), is dried, filtered and is concentrated with sodium sulphate.It should Residue is purified with preparative-HPLC, obtains N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyan Base -4- ethylpyridine -2- base) azetidine -3- base) -2- hydroxyl acetamide (90mg, 34% yield) is white solid. LCMS m/z=451.0 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.56 (d, J=7.23Hz, 1H), 7.84 (s, 1H), 7.57-7.47 (m, 2H), 7.39-7.29 (m, 3H), 7.23 (s, 1H), 5.57-5.50 (m, 2H), 4.80-4.59 (m, 3H), 4.38 (br s, 2H), 3.86 (d, J=5.70Hz, 2H), 2.70 (q, J=7.45Hz, 2H), 1.18 (t, J=7.6Hz, 3H)。
Embodiment 289:
(S) -2- amino -3 Methylbutanoic acid 1- (6- ((4- (acetylamino methyl) benzyl) sulfenyl) -3,5- dicyano -4- Ethylpyridine -2- base) piperidin-4-yl ester
The chloro- 4- ethyl -6- of step 1:2- (4- hydroxy piperidine -1- base) pyridine -3,5- dimethoxy nitrile
To chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in embodiment 3, step 2,2g, 8.67mmol) and piperidines -4- alcohol is added in TEA (2.417mL, 17.34mmol) in the cooling solution in methylene chloride (40mL) (0.877g, 8.67mmol).The reaction mixture is stirred at room temperature 30 minutes.The reaction mixture is dilute with DCM (60mL) It releases.Organic layer is washed with water (50mL) and saturated brine solution (50mL).Finally is dried, filtered and steamed with anhydrous sodium sulfate Hair, obtaining the chloro- 4- ethyl -6- of 2- (4- hydroxy piperidine -1- base) pyridine -3,5- dimethoxy nitrile, (2.2g, 7.17mmol, 83% are produced Rate), it is pale solid.LCMS m/z=291.2 [M+H]+。
Step 2:N- (4- (((3,5- dicyano -4- ethyl -6- (4- hydroxy piperidine -1- base) pyridine -2- base) sulfenyl) first Base) benzyl) acetamide
To the chloro- 4- ethyl -6- of 2- (4- hydroxy piperidine -1- base) pyridine -3,5- dimethoxy nitrile (1g, 3.27mmol) in N, N- Thioacetic acid potassium (0.746g, 6.53mmol) is added in agitating solution in dimethylformamide (10mL) and by gained mixture It is stirred at room temperature 2 hours.Then potassium carbonate (0.903g, 6.53mmol) and N- (4- (bromomethyl) benzyl) acetamide is added (3.16g, 3.27mmol) and the reaction mixture is stirred at room temperature 1 hour.The organic phase is dilute with ethyl acetate (200mL) It releases and HCl (1N, 2x 100mL) is used to wash.By organic layer anhydrous Na2SO4It dries, filters and evaporates.Raw product is passed through Silica gel chromatography (100-200 mesh, with the hexanes of 50% ethyl acetate), obtains N- (4- (((3,5- dicyan Base -4- ethyl -6- (4- hydroxy piperidine -1- base) pyridine -2- base) sulfenyl) methyl) benzyl) acetamide (1g, 67% yield), For pale solid.LCMS m/z=450.2 [M+H]+。
Step 3:(S) -2- ((tertbutyloxycarbonyl) amino) -3 Methylbutanoic acid 1- (6- ((4- (acetylamino methyl) benzyl Base) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl ester
To 2,4,6- trichloro-benzoyl chlorides (269mg, 1.101mmol), (S) -2- ((tertbutyloxycarbonyl) amino) -3- first Base butyric acid (478mg, 2.202mmol) is added in the solution in n,N-Dimethylformamide (2mL) and tetrahydrofuran (20mL) Triethylamine (0.153mL, 1.101mmol) then stirs the reaction 5 hours at 0 DEG C.In 0 DEG C of addition N- (4- (((3,5- bis- Cyano -4- ethyl -6- (4- hydroxy piperidine -1- base) pyridine -2- base) sulfenyl) methyl) benzyl) acetamide (500mg, 1.101mmol) and DMAP (135mg, 1.101mmol) and the reaction mixture is stirred at room temperature 1 hour.The reaction is mixed Object is quenched with ice cold water (100mL) and is extracted with ethyl acetate (2x 100mL).By combined organic layer anhydrous Na2SO4It is dry It is dry, filtering and evaporation.By raw product, by silica gel chromatography, (100-200 mesh is washed with the hexane of 20% ethyl acetate It is de-), obtain (S) -2- ((tertbutyloxycarbonyl) amino) -3 Methylbutanoic acid 1- (6- ((4- (acetylamino methyl) benzyl) sulfenyl) - 3,5- dicyano -4- ethylpyridine -2- bases) piperidin-4-yl ester (450mg, 61% yield) is light yellow solid.LCMS m/ Z=649.4 [M+H]+。
Step 4:(S) -2- amino -3 Methylbutanoic acid 1- (6- ((4- (acetylamino methyl) benzyl) sulfenyl) -3,5- two Cyano -4- ethylpyridine -2- base) piperidin-4-yl ester
At 0 DEG C, to (S) -2- ((tertbutyloxycarbonyl) amino) -3 Methylbutanoic acid 1- (6- ((4- (acetylamino methyl) benzyl Base) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl ester (450mg, 0.666mmol) is in Isosorbide-5-Nitrae-dioxanes It is added in agitating solution in (5mL) HCl (4M in Isosorbide-5-Nitrae-dioxanes, 5mL, 20mmol), then the reaction mixture exists It is stirred at room temperature 45 minutes.The reaction mixture is concentrated under reduced pressure and purifies thick material preparative-HPLC, is obtained (S) -2- amino -3 Methylbutanoic acid 1- (6- ((4- (acetylamino methyl) benzyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) piperidin-4-yl ester (135mg, 36% yield) is white solid.LCMS m/z=549.2 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.32-8.23 (m, 1H), 7.35 (d, J=8.11Hz, 2H), 7.20 (d, J=8.11Hz, 2H), 5.11-4.97 (m, 1H), 4.47 (s, 2H), 4.21 (d, J=5.92Hz, 2H), 4.11-3.98 (m, 2H), 3.85-3.71 (m, 2H), 3.13 (d, J=5.48Hz, 1H), 2.77 (q, J=7.23Hz, 2H), 1.99 (br dd, J=12.93,3.51Hz, 2H), 1.93-1.81 (m, 4H), 1.69 (br d, J=3.07Hz, 4H), 1.22 (t, J=7.56Hz, 3H), 0.87 (dd, J= 19.07,6.80Hz, 6H).
Embodiment 290
N- (1- (6- ((4- (acetylamino methyl) benzyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperazine Pyridine -4- base) acetamide
Step 1:(1- (6- ((4- (acetylamino methyl) benzyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) Piperidin-4-yl) t-butyl carbamate
At -20 DEG C, (conjunction is described in embodiment 3, step 2 to chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- Be added in the suspension in ethyl alcohol (1mL) at 100mg, 0.442mmol) piperidin-4-yl t-butyl carbamate (97mg, 0.487mmol) the solution in ethyl alcohol (1mL).Then the reaction mixture is stirred 1 hour at -20 DEG C.Then to the reaction Thioacetic acid potassium (76mg, 0.664mmol) and Et are added in mixture3N (0.154mL, 1.106mmol).Then this is non- Phase reaction mixture is warmed to 20 DEG C and is stirred overnight mutually synthermal.N- (4- (bromomethyl) is added into the reaction mixture Benzyl) acetamide (107mg, 0.442mmol).The reaction is continued to stir at 20 DEG C.After stirring 2.5 hours, which is mixed Object filtering is closed, solid is washed and abandoned.The filtrate is concentrated, resulting materials reversed-phase HPLC is purified into (Gilson, 30mm x 50mm Gemini column, NH4OH modifying agent), obtain (1- (6- ((4- (acetylamino methyl) benzyl) sulfenyl) -3,5- dicyano - 4- ethylpyridine -2- base) piperidin-4-yl) t-butyl carbamate (95mg, 0.173mmol, 39% yield).LCMS m/z= 545.4[M+Na]+。
Step 2:N- (4- (((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) first Base) benzyl) acetamide
By (1- (6- ((4- (acetylamino methyl) benzyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperazine Pyridine -4- base) t-butyl carbamate (78mg, 0.142mmol) is in the dioxane of 4M HCl (2000 μ l, 8.0mmol) Suspension be stirred at room temperature 1.5 hours, then the reaction mixture is concentrated.Resulting materials are suspended in MeOH and use isopropyl Amine is free-basing, and A-CN is needed to be purified to be redissolved material.The mixture reversed-phase HPLC is purified into (Gilson, 30mm X 50mm Gemini column, NH4OH modifying agent), obtain N- (4- (((6- (4- amino piperidine -1- base) -3,5- dicyano -4- second Yl pyridines -2- base) sulfenyl) methyl) benzyl) acetamide (59mg) is white solid.LCMS m/z=449.5 [M+H]+。
Step 3:N- (1- (6- ((4- (acetylamino methyl) benzyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) piperidin-4-yl) acetamide
In room temperature, to N- (4- (((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) methyl) benzyl) acetamide (20mg, 0.045mmol) and DIEA (8.57 μ l, 0.049mmol) it is molten in chloroform (1mL) Acetic anhydride (4.63 μ l, 0.049mmol) is added in liquid.Then the reaction mixture is stirred at room temperature 2 hours.Then by the reaction Mixture is concentrated by rotary evaporation.The faint yellow oil of gained is purified with reversed-phase HPLC, obtains N- (1- (6- ((4- (acetylamino Methyl) benzyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl) acetamide (19mg), it is solid for white Body.LCMS m/z=491.5 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.34 (t, J=5.83Hz, 1H), 7.90 (d, J=7.60Hz, 1H), 7.34-7.38 (m, J=8.11Hz, 2H), 7.19-7.23 (m, J=8.11Hz, 2H), 4.47 (s, 2H), 4.40 (d, J=13.18Hz, 2H), 4.21 (d, J=5.83Hz, 2H), 3.90 (dd, J=3.55,7.35Hz, 1H), 2.77 (q, J=7.60Hz, 2H), 1.87-1.93 (m, 2H), 1.86 (s, 3H), 1.81 (s, 3H), 1.37-1.50 (m, 2H), 1.21 (t, J=7.60Hz, 3H).Two protons do not measure.
Embodiment 291
2- (4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl) phenyl)-N- (2- hydroxyethyl) acetamide
Step 1:(2- (4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl) Phenyl) acetic acid
At 0 DEG C, to 2- (dimethylamino) -4- ethyl -6- mercaptopyridine -3,5- dimethoxy nitrile (in embodiment 92, step 3 In describe synthesis, 232mg, 0.999mmol) and Et3N (0.139mL, 0.999mmol) is in the suspension in chloroform (1mL) 2- (4- (bromomethyl) phenyl) solution of acetic acid (229mg, 0.999mmol) in chloroform (4.0mL) is added.Then by the reaction Mixture is stirred overnight at 0 DEG C.The reaction mixture is warmed to room temperature and is concentrated.The thick material is purified with reversed-phase HPLC (Gilson, 30mm Gemini column, NH4OH modifying agent), obtain (2- (4- (((3,5- dicyano -6- (dimethylamino) -4- Ethylpyridine -2- base) sulfenyl) methyl) phenyl) acetic acid (246mg) is white solid LCMS m/z=381.2 [M+H]+。
Step 2:2- (4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl) benzene Base)-N- (2- hydroxyethyl) acetamide
In room temperature, to (2- (4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) first Base) phenyl) acetic acid (67mg, 0.176mmol) be added in the solution in n,N-Dimethylformamide (1.5mL) HATU (67mg, 0.176mmol).Then the reaction mixture is stirred at room temperature 30 minutes, be added at this time ethanol amine (0.021mL, 0.352mmol) and Et3N (0.025mL, 0.176mmol).Then the reaction mixture is stirred overnight at 40 DEG C, it then will be anti- It answers mixture to be cooled to room temperature, filter and purifies (Gilson, 30mm x 50mm Gemini column, NH with reversed-phase HPLC4OH is modified Agent), obtain 2- (4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl) phenyl)-N- (2- hydroxyethyl) acetamide (54mg), is white solid.LCMS m/z=424.4 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.07 (t, J=5.45Hz, 1H), 7.31-7.35 (m, J=8.11Hz, 2H), 7.19-7.23 (m, J= 8.11Hz, 2H), 4.69 (t, J=5.20Hz, 1H), 4.49 (s, 2H), 3.36-3.42 (m, 4H), 3.10 (q, J=5.91Hz, 2H), 2.76 (q, J=7.60Hz, 2H), 1.21 (t, J=7.60Hz, 3H).6 protons do not measure.
Embodiment 292
4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl)-N- (2- hydroxyl Ethyl) benzamide
Step 1:4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl) benzene first Acid
At 0 DEG C, to 2- (dimethylamino) -4- ethyl -6- mercaptopyridine -3,5- dimethoxy nitrile (in embodiment 92, step 3 In describe synthesis, 232mg, 0.999mmol) and Et3N (0.139mL, 0.999mmol) is in the suspension in chloroform (1mL) The solution of 4- (bromomethyl) benzoic acid (215mg, 0.999mmol) in chloroform (4.0mL) is added.Then by the reaction mixture It is stirred overnight at 0 DEG C.After 0 DEG C is stirred overnight, which is warmed to room temperature and be concentrated.By the thick material reverse phase HPLC purifies (Gilson, 30mm Gemini column, NH4OH modifying agent), obtain 4- (((3,5- dicyano -6- (dimethylaminos Base) -4- ethylpyridine -2- base) sulfenyl) methyl) benzoic acid (331mg) is sticky white solid.LCMS m/z=367.2 [M+H]+。
Step 2:4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl)-N- (2- hydroxyethyl) benzamide
In room temperature, to 4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl) benzene Formic acid (65mg, 0.177mmol)) in the solution in n,N-Dimethylformamide (1.5mL) be added HATU (67mg, 0.176mmol).Then the reaction mixture is stirred at room temperature 30 minutes, be added at this time ethanol amine (0.021mL, 0.352mmol) and Et3N (0.025mL, 0.176mmol).Then the reaction mixture is stirred overnight at 40 DEG C, it then will be anti- It answers mixture to be cooled to room temperature, filter and purifies (Gilson, 30mm x 50mm Gemini column, NH with reversed-phase HPLC4OH is modified Agent), obtain 4- (((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl)-N- (2- hydroxyl second Base) benzamide (47mg) is white solid.LCMS m/z=410.3 [M+H]+。1H NMR (400MHz, DMSO-d6)δ Ppm 8.43 (t, J=5.58Hz, 1H), 7.79-7.83 (m, 2H), 7.47-7.51 (m, J=8.36Hz, 2H), 4.70-4.78 (m, 1H), 4.57 (s, 2H), 3.50 (q, J=5.49Hz, 2H), 3.31 (s, 6H), 3.29-3.33 (m, 2H), 2.77 (q, J= 7.60Hz, 2H), 1.21 (t, J=7.60Hz, 3H)
Embodiment 293:
2- ((3- cyano -4- ethyl -5- methyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides
Step 1:4- ethyl -2,6- dihydroxy -5- picoline -3- formonitrile HCN
Exist to 2- methyl -3- oxopentanoic acid methyl ester (5g, 31.6mmol) and 2- cyanoacetamide (2.66g, 31.6mmol) The solution of KOH (1.951g, 34.8mmol) in 50mL MeOH is added in solution in methanol (50mL).The mixture is stirred It mixes and is refluxed overnight.The mixture is filtered.Solid is dissolved in 50mL hot water, then pH to pH 2 is adjusted with dense HCl, then filters And be dried in vacuo, obtain required product 4- ethyl -2,6- dihydroxy -5- picoline -3- formonitrile HCN (1.25g, 7.02mmol, 22.19% yield), it is white solid.1H NMR (400MHz, DMSO) δ 11.20 (s, 2H), 2.62 (q, J=8Hz, 2H), 1.95 (s, 3H), 1.12 (t, J=8Hz, 3H).
The chloro- 4- ethyl -5- picoline -3- formonitrile HCN of step 2:2,6- bis-
By 4- ethyl -2,6- dihydroxy -5- picoline -3- formonitrile HCN (2.5g, 14.03mmol) in phosphorus oxychloride Solution in (15mL) is stirred overnight at 150 DEG C, is then concentrated in vacuo.The residue is diluted with DCM (50mL), uses saturated water NH4Cl, salt water (50mL) washing, use Na2SO4It dries, filters and is dried in vacuo, obtain the chloro- 4- ethyl -5- methyl pyrrole of 2,6- bis- Pyridine -3- formonitrile HCN (650mg, 3.02mmol), is yellow solid.1H NMR (400MHz, CDCl3) δ ppm 2.97 (q, J= 7.6Hz, 2H), 2.43 (s, 3H), 1.29 (t, J=7.6Hz, 3H).
Step 3:4- (the chloro- 5- cyano -4- ethyl -3- picoline -2- base of 6-) piperazine -1- t-butyl formate
To the chloro- 4- ethyl -5- picoline -3- formonitrile HCN (440mg, 2.05mmol) of 2,6- bis- in acetonitrile (20mL) Piperazine -1- t-butyl formate (381mg, 2.05mmol) and triethylamine (0.570mL, 4.09mmol) are added in solution.This is mixed Object is closed to be stirred overnight in 120 DEG C of sealed tubes.The mixture is concentrated in vacuo, by residue flash column chromatography (stone Oily ether: EtOAc=4:1), obtain 4- (the chloro- 5- cyano -4- ethyl -3- picoline -2- base of 6-) piperazine -1- t-butyl formate (560mg, 1.54mmol, 75% yield), is yellow solid.LCMS m/z=387.0 [M+Na]+。
Step 4:4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -5- cyano -4- ethyl -3- methyl pyrrole Pyridine -2- base) piperazine -1- t-butyl formate
To 4- (the chloro- 5- cyano -4- ethyl -3- picoline -2- base of 6-) piperazine -1- t-butyl formate (500mg, 2- sulfydryl -2- phenyl-acetamides 1.37mmol) are added in the solution in N,N-dimethylformamide (15mL) (in embodiment Synthesis, 687mg, 4.11mmol are described in 276 steps 1), KI (455mg, 2.74mmol) and triethylamine (0.573mL, 4.11mmol).The mixture is stirred 1.5 hours in microwave reactor under 60 DEG C of nitrogen, is then concentrated in vacuo.This is residual Residue with ethyl acetate (100mL) dissolution, is washed with salt water (100mL x 2), uses Na2SO4It dries, filters and is evaporated in vacuo.It will The residue obtains 4- (6- ((2- amino -2- oxo -1- phenyl second with flash column chromatography (petroleum ether: EtOAc=1:1) Base) sulfenyl) -5- cyano -4- ethyl -3- picoline -2- base) piperazine -1- t-butyl formate (160mg, 0.32mmol, 24% Yield).LCMS:m/z=496.2 [M+H]+。
Step 5:2- ((3- cyano -4- ethyl -5- methyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl second Amide
To 4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -5- cyano -4- ethyl -3- picoline -2- Base) trifluoroacetic acid is added in the solution in methylene chloride (20mL) in piperazine -1- t-butyl formate (120mg, 0.24mmol) (1mL, 12.98mmol).The mixture is stirred at room temperature 2 hours.The mixture is concentrated in vacuo, by the residue acetic acid Ethyl ester (100mL) dissolution, with saturation NaHCO3Aqueous solution (50mL), salt water (50mL x 2) washing, use Na2SO4It dries, filters And it is concentrated in vacuo.By the residue with silica gel column purification (DCM:MeOH=20:1~10:1), 2- ((3- cyano -4- second is obtained Base -5- methyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides (20mg, 0.051mmol, 21% yield), It is yellow solid.LCMS m/z=396.3 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm δ 7.88 (b, 1H), 7.53 (m, 2H), 7.40-7.28 (m, 3H), 7.25 (b, 1H), 5.59 (s, 1H), 3.51 (s, 1H), 3.25-3.08 (m, 4H), 2.81 (m, 4H), 2.69-2.63 (m, 2H), 2.12 (s, 3H), 1.11 (t, J=7.6Hz, 3H).
Embodiment 294
2- ((4- (1H- imidazoles -1- base) benzyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- Base) pyridine -3,5- dimethoxy nitrile
Step 1:1- (4- (chloromethyl) phenyl) -1H- imidazoles
At 20 DEG C, to (4- (1H- imidazoles -1- base) phenyl) methanol (100mg, 0.574mmol), DIEA (0.110mL, 0.631mmol) and methanesulfonic acid acid anhydride is added in the solution in methylene chloride (2.5mL) in DMAP (7.01mg, 0.057mmol) (110mg, 0.631mmol).Then the reaction mixture is warmed to 20 DEG C and is stirred 3 hours mutually synthermal, at this time should Reaction mixture dilutes with DCM and uses 1N HCl (2x), saturated brine (1x), is then washed with water.Water layer is concentrated, is obtained thick 1- (4- (chloromethyl) phenyl) -1H- imidazoles (328mg) processed is oil-solid mixture.LCMS m/z=193.1 [M+H]+。
Step 2:2- ((4- (1H- imidazoles -1- base) benzyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- diaza cycloheptyl Alkane -1- base) pyridine -3,5- dimethoxy nitrile
In room temperature, to 4- ethyl -2- sulfydryl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -3,5- diformazan Nitrile (synthesis, 104mg, 0.344mmol are described in embodiment 69, step 1) and Et3N (0.060mL, 0.430mmol) in N, Crude 1- (4- (chloromethyl) phenyl) -1H- imidazoles (83mg) is added in solution in dinethylformamide (3mL).Then The reaction mixture is stirred at room temperature 2 hours.The reaction mixture is filtered and purifies (Gilson, 30mm with reversed-phase HPLC Gemini column, NH4OH modifying agent), obtain 2- ((4- (1H- imidazoles -1- base) benzyl) sulfenyl) -4- ethyl -6- (4- methyl-1, 4- Diazesuberane -1- base) pyridine -3,5- dimethoxy nitrile (38mg) is pale beige solid.LCMS m/z=458.3 [M+H ]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.25 (t, J=1.14Hz, 1H), 7.74 (t, J=1.39Hz, 1H), 7.61- 7.66 (m, 2H), 7.52-7.56 (m, 2H), 7.09-7.12 (m, 1H), 4.56 (s, 2H), 3.84-3.93 (m, 4H), 2.79 (q, J=7.60Hz, 2H), 2.59-2.64 (m, 2H), 2.45-2.49 (m, 2H), 2.21 (s, 3H), 1.89-1.97 (m, 2H), 1.23 (t, J=7.60Hz, 3H)
Embodiment 295
2- ((4- cyano -3- methylbenzyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) Pyridine -3,5- dimethoxy nitrile
At -20 DEG C, (conjunction is described in embodiment 3, step 2 to chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- 1- methyl-1,4- Diazesuberane are added in the suspension in ethyl alcohol (3mL) at 300mg, 1.327mmol) The solution of (0.173mL, 1.393mmol) in ethyl alcohol (5mL).Then the reaction mixture is stirred 15 minutes at -20 DEG C.So Thioacetic acid potassium (227mg, 1.991mmol) and Et is added in the backward reaction mixture3N (0.647mL, 4.64mmol).So The heterogeneous reaction mixture is warmed to 40 DEG C afterwards and is stirred overnight mutually synthermal.4- is added into the reaction mixture (bromomethyl) -2- methyl-benzonitrile (558mg, 2.65mmol).The reaction is continued to stir at 40 DEG C.It is stirred 1.5 hours at 40 DEG C Afterwards, which is cooled to room temperature and is concentrated.The thick material is initially purified into (Biotage with normal-phase chromatography Isolera, 100g SNAP ULTRA column, hexane/EtOAc are rinsed with DCM/MeOH), then use reversed-phase HPLC repurity (Gilson, 30mm x 50mm Gemini column, NH4OH modifying agent), obtain 2- ((4- cyano -3- methylbenzyl) sulfenyl) -4- Ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -3,5- dimethoxy nitrile (179mg), is yellow oil.LCMS M/z=431.4 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.74 (d, J=8.11Hz, 1H), 7.50 (s, 1H), 7.38-7.43 (m, 1H), 4.55 (s, 2H), 3.77-3.88 (m, 4H), 2.78 (q, J=7.60Hz, 2H), 2.47 (s, 3H), 2.42-2.46 (m, 2H), 2.21 (s, 3H), 1.86-1.93 (m, 2H), 1.22 (t, J=7.60Hz, 3H).Two protons are not surveyed It arrives.
Embodiment 296
(4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) methyl) phenyl) t-butyl carbamate
To 4- ethyl -2- sulfydryl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -3,5- dimethoxy nitrile (4- (bromomethyl) benzene is added dropwise in (600mg, 1.493mmol) and TEA (0.416mL, 2.99mmol) in the solution in DMF (5mL) Base) solution of the t-butyl carbamate (427mg, 1.493mmol) in DMF (2mL).The reaction mixture is stirred at room temperature 30 minutes.The reaction mixture is diluted with water (30mL) and filters the solid.By the solid silica gel purification (ComiFlash, 24g column, use 0-10%MeOH/DCM), obtains pale solid.A part of material is pure with RP-HPLC Change (40-70% acetonitrile/water, 0.1%NH4OH is in water), obtain (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1, 4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) methyl) phenyl) t-butyl carbamate (10mg) is canescence Solid.LCMS m/z=507.3 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 1.19-1.24 (m, 3H), 1.47 (s, 9H), 1.89-1.99 (m, 2H), 2.24 (s, 3H), 2.47 (br.s., 2H), 2.61-2.68 (m, 2H), 2.78 (q, J= 7.6Hz, 2H), 3.85-3.94 (m, 4H), 4.42 (s, 2H), 7.27 (m, J=8.6Hz, 2H), 7.41 (m, J=8.6Hz, 2H), 9.38 (s, 1H).
Embodiment 297
2- ((4- aminobenzyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -3, 5- dimethoxy nitrile
By (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) phenyl) t-butyl carbamate (synthesis is described in embodiment 296) DCM (3mL) and TFA (1.5mL) Processing 1 hour, which is concentrated and uses NH4OH alkalization, then concentration and with silica gel column purification (24g column, uses 0-10%MeOH/DCM), obtain 2- ((4- aminobenzyl) sulfenyl) -4- ethyl -6- (4- Methyl-1,4- Diazesuberane -1- base) pyridine -3,5- dimethoxy nitrile (278mg, 0.684mmol, 46% yield) is greyish white Color solid.LCMS m/z=407.2 [M+H]+.1H NMR (400MHz, DMSO-d6) δ ppm 1.22 (t, J=7.6Hz, 3H), 1.89-2.00 (m, 2H), 2.26 (s, 3H), 2.49 (br.s., 2H), 2.66-2.73 (m, 2H), 2.77 (q, J=7.6Hz, 2H), 3.88-3.97 (m, 4H), 4.33 (s, 2H), 5.12 (s, 2H), 6.48-6.54 (m, 2H), 7.04 (d, J=8.4Hz, 2H)。
Embodiment 298
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) phenyl) acetamide
At 0 DEG C, to 2- ((4- aminobenzyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) Pyridine -3,5- dimethoxy nitrile (synthesis, 60mg, 0.148mmol are described in embodiment 297) drips in the solution in THF (2mL) Add solution of the chloroacetic chloride (0.014mL, 0.192mmol) in THF (0.5mL).The reaction mixture is stirred 30 minutes.It should Reaction mixture is concentrated and uses RP-HPLC (30-60% acetonitrile/water, 0.1%NH4OH is in water) purifying, obtain N- (4- (((3, 5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) methyl) phenyl) acetyl Amine (43mg, 0.096mmol, 65% yield), is pale solid.LCMS m/z=449.3 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 1.22 (t, J=7.6Hz, 3H), 1.88-1.98 (m, 2H), 2.03 (s, 3H), 2.24 (s, 3H), 2.49-2.46 (m, 2H), 2.59-2.70 (m, 2H), 2.78 (q, J=7.6Hz, 2H), 3.84-3.95 (m, 4H), 4.44 (s, 2H), 7.31 (m, J=8.6Hz, 2H), 7.53 (m, J=8.6Hz, 2H), 9.97 (s, 1H).
Embodiment 299
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) phenyl) methylsulfonamides
At 0 DEG C, to 2- ((4- aminobenzyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) Pyridine -3,5- dimethoxy nitrile (synthesis, 60mg, 0.148mmol are described in embodiment 297) and TEA (0.062mL, Mesyl chloride (0.017mL, 0.221mmol) 0.443mmol) is added dropwise in the solution in THF (3mL) in THF (0.5mL) Solution.The reaction mixture is stirred 30 minutes.The reaction mixture is concentrated and purified with RP-HPLC (20-60% acetonitrile/ Water, 0.1%NH4OH is in water), obtain N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- diaza cycloheptyls Alkane -1- base) pyridine -2- base) sulfenyl) methyl) phenyl) methylsulfonamides (38mg, 0.078mmol, 53% yield), for white Solid.LCMS m/z=485.3 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 1.22 (t, J=7.6Hz, 3H), 1.85-1.99 (m, 2H), 2.24 (s, 3H), 2.49-2.46 (m, 2H), 2.63-2.68 (m, 2H), 2.78 (q, J=7.6Hz, 2H), 2.96 (s, 3H), 3.83-3.95 6 (m, 4H), 4.45 (s, 2H), 7.12-7.17 (m, 2H), 7.35 (d, J=8.6Hz, 2H).1 proton does not measure.
Embodiment 300
2- (((6- aminopyridine -3- base) methyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- Base) pyridine -3,5- dimethoxy nitrile
At 0 DEG C, to 4- ethyl -2- sulfydryl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -3,5- diformazan Nitrile (761mg, 2.020mmol) and TEA (0.563mL, 4.04mmol) are slowly added to (5- (bromine in the solution in DMF (6mL) Methyl) pyridine -2- base) t-butyl carbamate (580mg, 2.020mmol) is in the pulp solution in DMF (5mL).This is anti- Mixture is answered gradually to warm to room temperature and be stirred overnight.The reaction mixture is diluted with water and DCM (2x) is used to extract.It will merge Organic matter water and salt water washing, use Na2SO4It is dry, be concentrated and with silica gel purification (40g column is used 100% hexane elution, is then eluted with 0-10%MeOH/DCM), obtain light yellow solid.To in the solid in DCM (3mL) It is added TFA (0.156mL, 2.020mmol).The reaction mixture is stirred 4 hours, is then concentrated and uses NH4OH aqueous solution (5mL) alkalization, is then extracted with EtOAc (3x).By combined organic matter water and salt water washing, Na is used2SO4It is dry, concentration, Obtain 2- (((6- aminopyridine -3- base) methyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyrrole Pyridine -3,5- dimethoxy nitrile (355mg, 0.871mmol, 43% yield), is light tan solid.LCMS m/z=408.2 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 1.22 (t, J=7.6Hz, 3H), 1.92-2.00 (m, 2H), 2.27 (s, 3H), 2.51-2.57 (m, 2H), 2.70 (br.s., 2H), 2.78 (q, J=7.6Hz, 2H), 3.87-3.97 (m, 4H), 4.33 (s, 2H), 5.98 (s, 2H), 6.37-6.45 (m, 1H), 7.38 (dd, J=8.4,2.5Hz, 1H), 7.92 (d, J=2.0Hz, 1H).
Embodiment 301
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) phenyl) -2- hydroxyl acetamide
By 2- ((4- aminobenzyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine - 3,5- dimethoxy nitriles (synthesis, 55mg, 0.135mmol are described in embodiment 297), 2- hydroxyacetic acid (30.9mg, 0.406mmol), EDC (38.9mg, 0.203mmol), 1- hydroxyl -7- azepine benzotriazole (27.6mg, 0.203mmol) and N- Solution of the methyl morpholine (0.045mL, 0.406mmol) in DMF (3mL) is stirred at room temperature overnight.The reaction mixture is used RP-HPLC purifies (20-50% acetonitrile/water, 0.1%NH4OH is in water), obtain N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) methyl) phenyl) -2- hydroxyl acetamide (20mg, 0.043mmol, 32% yield), it is white solid.LCMS m/z=465.3 [M+H]+。1H NMR (400MHz, DMSO-d6)δ Ppm 1.22 (t, J=7.6Hz, 3H), 1.84-2.02 (m, 2H), 2.24 (s, 3H), 2.49-2.46 (m, 2H), 2.60-2.70 (m, 2H), 2.78 (q, J=7.6Hz, 2H), 3.84-3.94 (m, 4H), 3.98 (d, J=3.8Hz, 2H), 4.45 (s, 2H), 5.68 (br.s., 1H), 7.33 (m, J=8.6Hz, 2H), 7.66 (m, J=8.6Hz, 2H), 9.70 (s, 1H).
Embodiment 302
2- amino-N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyrrole Pyridine -2- base) sulfenyl) methyl) phenyl) acetamide
By 2- ((4- aminobenzyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine - 3,5- dimethoxy nitriles (synthesis, 55mg, 0.135mmol are described in embodiment 297), 2- ((tertbutyloxycarbonyl) amino) acetic acid (71.1mg, 0.406mmol), EDC (38.9mg, 0.203mmol), 1- hydroxyl -7- azepine benzotriazole (27.6mg, 0.203mmol) it is stirred at room temperature overnight with the solution of N-methylmorpholine (0.045mL, 0.406mmol) in DMF (2mL).It will Reaction mixture RP-HPLC purifies (30-70% acetonitrile/water, 0.1%NH4OH is in water), obtain light yellow solid.To TFA (1mL) is added in solid in DCM (2mL), stirs 1 hour.The reaction mixture is concentrated and with TEA alkalization and again Concentration.Residue RP-HPLC is purified into (5-40% acetonitrile/water, 0.1%NH4The aqueous solution of OH), obtain 2- amino-N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) methyl) Phenyl) acetamide (22mg, 0.047mmol, 35% yield) is pale solid.LCMS m/z=464.3 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 1.22 (t, J=7.6Hz, 3H), 1.88-1.99 (m, 2H), 2.24 (s, 3H), 2.47- 2.49 (m, 2H), 2.60-2.69 (m, 2H), 2.78 (q, J=7.6Hz, 2H), 3.25 (s, 2H), 3.82-6 3.96 (m, 4H), 4.45 (s, 2H), 7.33 (m, J=8.6Hz, 2H), 7.60 (m, J=8.6Hz, 2H).Three protons do not measure.
Embodiment 303
2- ((3,5- dicyano -4- ethyl -6- (5- methyl -2,5- diazabicyclo [2.2.1] hept- 2- yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides
The chloro- 4- ethyl -6- of step 1:2- (5- methyl -2,5- diazabicyclo [2.2.1] hept- 2- yl) pyridine -3,5- two Formonitrile HCN
To 2- methyl -2,5- diazabicyclo [2.2.1] heptane, dihydrobromide (974mg, 3.55mmol) is in dichloro Triethylamine (2.477mL, 17.77mmol) is added in agitating solution in methane (30mL) and is stirred at room temperature 10 minutes.By 2, Bis- chloro- 4- ethylpyridine -3,5- dimethoxy nitrile (describing synthesis, 800mg, 3.54mmol in 3 step 2 of embodiment) of 6- adds to this In reaction mixture and it is stirred at room temperature 16 hours.The reaction mixture is quenched with water (40mL) and is extracted with DCM (2x 50mL) It takes.Combined organic layer water (40mL), saline solution (40mL) are washed, anhydrous Na is used2SO4It dries, filters and depressurizes dense Contracting, obtains crude compound.By the crude material with silica gel chromatography (100-200 mesh, eluant, eluent 3%MeOH/DCM), obtain To the chloro- 4- ethyl -6- of 2- (5- methyl -2,5- diazabicyclo [2.2.1] hept- 2- yl) pyridine -3,5- dimethoxy nitrile (600mg), It is faint yellow solid.LCMS m/z=302.2 [M+H]+。
Step 2:2- ((3,5- dicyano -4- ethyl -6- (5- methyl -2,5- diazabicyclo [2.2.1] hept- 2- yl) Pyridine -2- base) sulfenyl) -2- phenyl-acetamides
Under nitrogen atmosphere, to the chloro- 4- ethyl -6- of 2- (5- methyl -2,5- diazabicyclo [2.2.1] hept- 2- yl) pyrrole Thioacetic acid potassium is added in the agitating solution in N,N-dimethylformamide (15mL) in pyridine -3,5- dimethoxy nitrile (550mg) (312mg, 2.73mmol).Gained reaction mixture is stirred at room temperature 30 minutes.Into the reaction be added potassium carbonate (378mg, 2.73mmol) and methanesulfonic acid 2- amino -2- oxo -1- phenylethylester (describe synthesis in 3 step 5 of embodiment, 418mg, 1.823mmol).Gained reaction mixture is stirred at room temperature 16 hours.The reaction mixture is diluted with ice cold water (30mL) And it is extracted with EtOAc (3x 30mL).Combined organic layer is washed with ice cold water (2x 30mL), saline solution (30mL) is washed It washs, uses anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure, obtain crude compound.By the crude material silica gel chromatography (100-200 mesh, eluant, eluent: 5%MeOH/DCM), obtains brown solid.The solid is washed with ether, filters and dries, obtain To 2- ((3,5- dicyano -4- ethyl -6- (5- methyl -2,5- diazabicyclo [2.2.1] hept- 2- yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides (335mg) are Light brown solid.LCMS m/z=433.2 [M+H]+。1H NMR (400MHz, chlorine Imitative-d) δ ppm 7.29-7.49 (m, 5H), 6.49-6.65 (m, 1H), 5.41-5.52 (m, 1H), 5.32 (d, J=7.2Hz, 1H), 5.17 (br s, 1H), 3.86-3.98 (m, 2H), 3.54 (s, 1H), 2.73-3.03 (m, 4H), 2.45 (s, 3H), 2.04 (d, J=10.3Hz, 1H), 1.83 (d, J=10.3Hz, 1H), 1.32 (t, J=7.6Hz, 3H).
Embodiment 304:
2- ((3,5- dicyano -4- ethyl -6- (4- (2- (pyrrolidin-1-yl) ethyl) piperazine -1- base) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides
By 2- [(the bromo- 3,5- dicyano -4- ethyl -2- pyridyl group of 6-) sulfanyl] -2- phenvl-acetamide (in embodiment 6, synthesis, 15mg, 0.04mmol are described in step 1) solution 1- [2- (pyrrolidinyl) ethyl] piperazine in THF (1mL) Piperazine (0.02mL, 0.09mmol) processing, is stirred at room temperature 18 hours, then loading to SiO2(0.9g) and in SiO2(4g RediSep column) on carry out chromatogram purification, with 0-10%MeOH, 0-1%NH3/ DCM elution, then uses Et2O grinding, obtains 2- [[3,5- dicyano -4- ethyl -6- [4- (2- pyrrolidin-1-yl ethyl) piperazine -1- base] -2- pyridyl group] sulfanyl] -2- benzene Base-acetamide (16mg, 85% yield), is faint yellow solid.LCMS m/z=504.3 [M+H]+。1H NMR (300MHz, DMSO-d6) δ ppm 7.91 (s, 1H), 7.55-7.48 (m, 2H), 7.42-7.31 (m, 4H), 5.53 (s, 1H), 3.93-3.78 (m, 4H), 3.34-3.32 (m, 4H), 2.75 (q, J=7.5Hz, 2H), 2.60-2.54 (m, 2H), 2.48-2.42 (m, 6H), 1.71-1.63 (m, 4H), 1.20 (t, J=7.6Hz, 3H).
Embodiment 305
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides -2-d
Step 1:2- phenyl-acetamides -2,2-d2
2- phenyl-acetamides (2g, 14.80mmol), K will be packed into 20-mL microwave vial2CO3(2.045g, 14.80mmol)、D2O (10mL, 553mmol).Bottle is sealed and is heated 30 minutes in 100 DEG C of microwave reactors.LCMS points Analysis indicates that the reaction does not complete, therefore the reaction is heated 15 minutes in 120 DEG C of microwave reactors.Lcms analysis instruction is good Conversion, about 25% is hydrolyzed into acid.By the reaction down to chloroform (50mL), separates and wash water layer with additional chloroform (20mL) It washs.Combined organic matter is dried, filtered with sodium sulphate, is concentrated, obtains 2- phenyl-acetamides -2,2-d2(1g), for white Solid.1H NMR analysis instruction 94.5%D is incorporated to.Above-mentioned white solid, K are packed into 20-mL microwave vial2CO3(0.256g, 1.850mmol)、D2O (10mL, 553mmol).Bottle is sealed and is heated 15 minutes in 120 DEG C of microwave reactors.This is anti- It should separate down to chloroform (50mL) and dry, filter organic layer with sodium sulphate, be concentrated, obtain 2- phenyl-acetamides -2,2-d2 (650mg, 4.74mmol, 32.0% yield), is white solid.1H NMR analysis instruction 99.3%D incorporation.LCMS m/z= 137.9[M+H]+。
The bromo- 2- phenyl-acetamides -2-d of step 2:2-
By 2- phenyl-acetamides -2,2-d2(400mg, 2.92mmol), N- bromine succinimide (778mg, 4.37mmol) It is assigned in 16 4mL screw cap vials in the solution in methylene chloride (32mL) and with Blue LED light, uses Aldrich (ALKIT001) low-light chemical reactor irradiates.The reaction is stirred 75 minutes.Lcms analysis indicates good conversion, therefore should Reaction merges, and is washed with water (2x 20mL), then dries, filters organic layer with sodium sulphate, is concentrated, residue is obtained, by it With purification by flash chromatography (0-50%EtOAc in hexane, 25-g column), obtain the bromo- 2- phenyl-acetamides -2-d of 2- (160mg, 0.744mmol, 26% yield), it is orange solids.LCMS m/z=214.8,216.9 [M+H]+。
Step 3:2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine -2-d
To the bromo- 2- phenyl-acetamides -2-d (46.3mg, 0.215mmol) of 2-, 2- (dimethylamino) -4- ethyl -6- mercapto Yl pyridines -3,5- dimethoxy nitrile (synthesis, 50mg, 0.215mmol are described in embodiment 92, step 3) is in N, N- dimethyl methyl Triethylamine (0.060mL, 0.430mmol) is added in solution in amide (1mL).The reaction is stirred at room temperature 7 minutes, then The mixture is poured into D2In O (5mL) and stir 10 minutes, then filtering and with additional D2O (5mL) washing, it is dry in pump It 1 hour, is then dried overnight in vacuum drying oven, obtains the gray solid of 70mg.The gray solid is suspended in H2O(5mL) In and be ultrasonically treated and filtering, obtain 2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides -2-d (61mg, 0.166mmol, 77% yield), is gray solid.LCMS m/z=367.1 [M+H]+。1H NMR(DMSO-d6) δ ppm 7.90-7.95 (m, 1H), 7.49-7.56 (m, 2H), 7.27-7.43 (m, 4H), 3.34 (s, 6H), 2.76 (d, J=7.6Hz, 2H), 1.20 (t, J=7.6Hz, 3H).6 protons do not measure.
Embodiment 308
(R) -2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine -2-d
By 2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides - 2-d (describing synthesis, about 50mg in 305 step 3 of embodiment) be dissolved in EtOH and purified with chirality HPLC (AD-H column, 40: 60 heptane: EtOH), obtain (R) -2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide -2-d (20mg, 0.055mmol), is white solid.Optical activity=- 308 ° (concentration=0.117, MeOH). LCMS m/z=367.1 [M+H]+。1H NMR(DMSO-d6) δ ppm 7.93 (s, 1H), 7.49-7.56 (m, 2H), 7.31-7.42 (m, 4H), 3.34 (s, 6H), 2.76 (q, J=7.6Hz, 2H), 1.16-1.24 (m, 3H).6 protons do not measure.
Embodiment 310:
2- ((6- (4- (4- benzoyl bromide) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides
By 2- [(3,5- dicyano -4- ethyl -6- piperazine -1- base -2- pyridyl group) sulfanyl] -2- phenvl-acetamide The suspension 4- bromo-benzoyl chloride of (synthesis, 18mg, 0.04mmol are described in embodiment 55) in DCM (2mL) The solution processing of (11mg, 0.05mmol) in DCM (0.5mL), obtains solution.Room temperature be added pyridine (0.007mL, 0.09mmol).After 90 minutes, solution of the additional 4- bromo-benzoyl chloride (3mg, 0.01mmol) in DCM (0.13mL) is added. Again after 90 minutes, which is diluted with EtOAc (15mL), with 2M HCl (10mL), water (10mL), 2M NaOH (10mL), Water (10mL) and salt water washing, it is then dry by Hydrophobic glass funnel.After vacuum concentration, by solid Et2O grinding, obtains To 2- [[6- [4- (4- benzoyl bromide) piperazine -1- base] -3,5- dicyano -4- ethyl -2- pyridyl group] sulfanyl] -2- benzene Base-acetamide (24mg, 92% yield), is white solid.LCMS m/z=587.1 [M-H]-.1H NMR (300MHz, DMSO-d6) δ ppm 7.86 (br s, 1H), 7.75-7.65 (m, 2H), 7.54-7.31 (m, 8H), 5.51 (s, 1H), 4.23- 3.85 (m, 4H), 3.80-3.64 (m, 2H), 3.62-3.45 (m, 2H), 2.85-2.72 (m, 2H), 1.21 (br t, J= 7.5Hz, 3H).
Embodiment 318:
2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base) pyridine - 2- yl) sulfenyl) -2- phenyl-acetamides
Step 1:4- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) -1,4- Diazesuberane -1- formic acid uncle Butyl ester:
At 0 DEG C, to chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (in 3 step 2 of embodiment describe synthesis, 1g, 4.17mmol) Isosorbide-5-Nitrae-Diazesuberane base -1- t-butyl formate is added in the agitating solution in methylene chloride (20mL) (0.834g, 4.17mmol), then triethylamine (0.581mL, 4.17mmol).The reaction is stirred at room temperature 1 hour.This is anti- It answers mixture to be concentrated under reduced pressure, diluted with water (40mL) and is extracted with methylene chloride (2x 100mL).By combined organic layer Use anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure, obtain 4- (chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-)-Isosorbide-5-Nitrae-two Azepan -1- t-butyl formate (1.2g), is brown solid.LCMS m/z=390.3 [M+H]+。
Step 2:4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) -1,4- Diazesuberane -1- t-butyl formate
To 4- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) -1,4- Diazesuberane -1- t-butyl formate (1g) thioacetic acid potassium (415mg, 3.63mmol) is added in the solution in n,N-Dimethylformamide (20mL) and mixes this Object is closed to be stirred at room temperature 2 hours.Then potassium carbonate (502mg, 3.63mmol) and methanesulfonic acid 2- amino -2- oxo -1- benzene is added Base ethyl ester (describing synthesis, 604mg, 2.423mmol in 3 step 5 of embodiment) simultaneously stirs the reaction mixture in room temperature It mixes 2 hours.The reaction mixture is quenched in cold water (10mL) and is extracted with ethyl acetate (2x 20mL).By having for merging Machine layer anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure, obtain 4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) - 3,5- dicyano -4- ethylpyridine -2- bases)-Isosorbide-5-Nitrae-Diazesuberane -1- t-butyl formate (1g) is brown solid. LCMS m/z=521.4 [M+H]+。
Step 3:2- ((3,5- dicyano -6- (1,4- Diazesuberane -1- base) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides
At 0 DEG C, to (4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) -1,4- Diazesuberane -1- t-butyl formate (900mg) is in the agitating solution in 1,4- dioxanes (15mL) It is added HCl (solution of the 4M in Isosorbide-5-Nitrae-dioxanes, 3.45mL, 13.81mmol) and the reaction mixture is small in 25 DEG C of stirrings 4 When.The reaction mixture is concentrated under reduced pressure, raw product is ground with ether (2x 40mL), filters and is dried in vacuo, obtain To 2- ((3,5- dicyano -6- (1,4- Diazesuberane -1- base) -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine, hydrochloride (600mg), is pale solid.LCMS m/z=421.4 [M+H]+。
Step 4:2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base) Pyridine -2- base) sulfenyl) -2- phenyl-acetamides
At 0 DEG C, to 2- ((3,5- dicyano -6- (Isosorbide-5-Nitrae-Diazesuberane -1- base) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides, triethylamine is added in the agitating solution in methylene chloride (10mL) in hydrochloride (300mg) Then ethylene bromohyrin (65.8mg, 0.527mmol) is added in (0.294mL, 2.107mmol).The reaction mixture is stirred at 25 DEG C It mixes 2 hours.The reaction mixture is concentrated under reduced pressure, then diluted with water (15mL) and is extracted with methylene chloride (2x 30mL) It takes.By combined organic layer anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure.The crude material is pure with preparative-HPLC Change, obtains 2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxyethyl)-Isosorbide-5-Nitrae-Diazesuberane -1- base) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides (80mg, 31% yield) are pale solid.LCMS m/z=465.3 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.91 (s, 1H), 7.49 (br d, J=7.02Hz, 2H), 7.40-7.23 (m, 4H), 5.51 (s, 1H), 4.38 (t, J=5.48Hz, 1H), 3.95-3.80 (m, 4H), 3.47 (q, J=5.92Hz, 2H), 2.88- 2.72 (m, 4H), 2.56-2.52 (m, 2H), 2.52-2.42 (m, 2H), 1.89 (br s, 2H), 1.21 (t, J=7.56Hz, 3H)。
Embodiment 319:
2- ((3,5- dicyano -6- (4- cyano piperidine -1- base) -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine
To 2- [(the bromo- 3,5- dicyano -4- ethyl -2- pyridyl group of 6-) sulfanyl] -2- phenvl-acetamide (in embodiment 6, synthesis, 40mg, 0.10mmol are described in step 1) and mixing of the triethylamine (0.03mL, 0.22mmol) in THF (2mL) 4- cyano piperidine (0.01mL, 0.11mmol) is added in object.Gained mixture is stirred at room temperature 17 hours.The mixture is used EtOAc (20mL) dilution, is washed with water (20mL), and water phase is extracted with EtOAc (20mL) and merges organic extract.It will extraction It takes object to be washed with salt water (2x 25mL) and filter by Hydrophobic glass and remove solvent under reduced pressure, obtains residue, used Et2O grinding is simultaneously dried in vacuo at 50 DEG C, obtains 2- [[3,5- dicyano -6- (4- cyano -1- piperidyl) -4- ethyl -2- pyridine Base] sulfanyl] -2- phenvl-acetamide (38mg, 89% yield) is orange powder.LCMS m/z=429.3 [M-H]-.1H NMR (300MHz, DMSO-d6) δ ppm 7.92 (br s, 1H), 7.55-7.49 (m, 2H), 7.43-7.32 (m, 4H), 5.52 (s, 1H), 4.19-4.07 (m, 2H), 3.71-3.57 (m, 2H), 3.28-3.17 (m, 1H), 2.77 (q, J=7.7Hz, 2H), 2.12- 1.98 (m, 2H), 1.88-1.70 (m, 2H), 1.21 (t, J=7.6Hz, 3H).
B applies example 320:
(S) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides
By 2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides (synthesis, 250mg, 0.62mmol are described in embodiment 168, step 3) are separated with chirality HPLC (chiralpak-IC column, HEX-EtOH (FA)) obtains (S) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxypyrroles Alkane -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides (29mg).LCMS m/z=408.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.91 (br s, 1H), 7.52 (br s, 1H), 7.52-7.49 (m, 1H), 7.45-7.25 (m, 4H), 5.61 (s, 1H), 5.14 (d, J=3.5Hz, 1H), 4.41 (s, 1H), 4.05-3.69 (m, 4H), 2.74 (q, J= 7.4Hz, 2H), 2.03-1.85 (m, 2H), 1.21 (q, J=7.4Hz, 3H).
Embodiment 321:
2- ((6- (4- amino -4- methyl piperidine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- Phenyl-acetamides
Step 1:(1- (the chloro- 3,5- dicyano -4- cyclopropyl pyridine -2- base of 6-) -4- methyl piperidine -4- base) amino first Tert-butyl acrylate
To chloro- 4- cyclopropyl pyridine -3, the 5- dimethoxy nitrile (333mg, 1.400mmol) of 2,6- bis- at methylene chloride (30mL) In solution in be added (4- methyl piperidine -4- base) t-butyl carbamate (300mg, 1.400mmol) and triethylamine (142mg, 1.400mmol).The mixture is stirred at room temperature 12 hours.The mixture is diluted with DCM (50mL), is washed with water and salt It washs, dries and concentrates, obtain crude (1- (chloro- 3, the 5- dicyano -4- cyclopropyl pyridine -2- base of 6-) -4- methyl piperidine -4- base) T-butyl carbamate (620mg), is brown oil.LCMS m/z=438.1 [M+Na]+。
Step 2:(1- (3,5- dicyano -4- cyclopropyl -6- mercaptopyridine -2- base) -4- methyl piperidine -4- base) amino T-butyl formate
To (1- (the chloro- 3,5- dicyano -4- cyclopropyl pyridine -2- base of 6-) -4- methyl piperidine -4- base) carbamic acid uncle Thioacetic acid potassium (204mg, 1.789mmol) is added in butyl ester (620mg) in the solution in DMF (4mL).By the mixture in room Temperature stirring 1 hour.By the reaction mixture n,N-Dimethylformamide (4mL) dilute and be added potassium carbonate (414mg, 3.00mmol).The mixture is stirred at room temperature 1 hour.Then methanesulfonic acid 2- amino -2- oxo -1- phenylethylester is added (516mg, 2.249mmol) and the mixture is stirred at room temperature 12 hours.The mixture water (80mL) is diluted and uses second Acetoacetic ester (30mL x 3) extraction.By combined organic layer water, salt water washing is dried and concentrated, and is obtained the crude product.It will The crude material obtains (1- (6- ((2- amino -2- oxygen by silica gel chromatography (using 1:2 ethyl acetate: petroleum ether elution) Generation -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine -2- base) -4- methyl piperidine -4- base) carbamic acid uncle Butyl ester (600mg).LCMS m/z=547.1 [M+H]+。
Step 3:2- ((6- (4- amino -4- methyl piperidine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulphur Base) -2- phenyl-acetamides, formates
By (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine -2- Base) -4- methyl piperidine -4- base) t-butyl carbamate (300mg) is dissolved in methylene chloride (DCM) (10mL) and trifluoroacetic acid In (1mL).The solution is stirred at room temperature 6 hours.The solution is concentrated, remaining residue preparative-HPLC is purified, Obtain 2- ((6- (4- amino -4- methyl piperidine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- phenyl Acetamide, formates (30mg) are shallow faint colour solid.LCMS m/z=447.1 [M+H]+。1H NMR (400MHz, DMSO- d6) δ ppm 8.35 (s, 1H), 7.97 (s, 1H), 7.55-7.49 (m, 2H), 7.45-7.30 (m, 4H), 5.53 (s, 1H), 3.99-3.89 (m, 2H), 3.88-3.76 (m, 2H), 2.16-2.07 (m, 1H), 1.73-1.57 (m, 4H), 1.26 (s, 3H), 1.18-1.07 (m, 2H), 1.02-0.93 (m, 2H).
Embodiment 322:
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (pyrrole Pyridine -2- base) acetamide
Step 1: methanesulfonic acid 2- amino -2- oxo -1- (pyridine -2- base) ethyl ester
In room temperature, to 2- hydroxyl -2- (pyridine -2- base) acetamide (300mg, 1.97mmol) and Et3N (0.55mL, Methane sulfonyl chloride (271mg, 2.37mmol) 3.94mmol) is added in the agitating solution in methylene chloride (10mL) and by gained Mixture is stirred at room temperature 5 hours.By the reaction mixture down in water (50mL) and with DCM (50mL x 2) extraction and closing And organic layer it is dry, concentration, obtaining methanesulfonic acid 2- amino -2- oxo -1- (pyridine -2- base) ethyl ester, (380mg, 84% produces Rate), it is pale solid.LCMS m/z=230.9 [M+H]+。
Step 2:2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulphur Base) -2- (pyridine -2- base) acetamide
By thioacetic acid potassium (149mg, 1.30mmol), the chloro- 4- ethyl -6- of (S) -2- (3- hydroxyl pyrrolidine -1- base) pyrrole Pyridine -3,5- dimethoxy nitrile (synthesis, 300mg, 1.08mmol are described in embodiment 168, step 1) is in n,N-Dimethylformamide Solution in (15mL) is stirred at room temperature 30 minutes, then by methanesulfonic acid 2- amino -2- oxo -1- (pyridine -2- base) ethyl ester (300mg, 1.30mmol) and Et3N (0.30mL, 2.17mmol) adds to the solution.The reaction mixture is stirred at room temperature 12 Hour.The reaction mixture is extracted down in water (50mL) and with EtOAc (50mL x 2).Combined organic layer is dry, Filtering is concentrated and (is eluted with DCM/MeOH 30/1) with silica gel column purification, obtains 2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (pyridine -2- base) acetamide (120mg, 27% yield), For white solid.LCMS m/z=408.9 [M+H]+。1H NMR (400MHz, DMSO) δ 8.54 (d, J=4.2Hz, 1H), 7.88 (br s, 1H), 7.83 (td, J=7.7,1.6Hz, 1H), 7.64 (d, J=7.8Hz, 1H), 7.40-7.31 (m, 2H), 5.73 (s, 1H), 5.18-5.04 (m, 1H), 4.39 (br s, 1H), 4.04-3.55 (m, 4H), 2.75 (q, J=7.5Hz, 2H), 2.10-1.85 (m, 2H), 1.21 (t, J=7.6Hz, 3H).
Embodiment 324
2- ((3,5- bis- chloro- 4- ethyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides
Step 1:4- (the chloro- 4- ethylpyridine -2- of 6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- two Base) piperazine -1- t-butyl formate
By 2- ((3,5- bis- chloro- 4- ethyl -6- fluorine pyridine -2- base) sulfenyl) -2- phenyl-acetamides (in embodiment 165, Synthesis, 100mg, 0.184mmol are described in step 2) and piperazine -1- t-butyl formate (49mg, 0.263mmol) add to bottle And it is suspended in dimethyl sulfoxide (3mL).The mixture is heated to 90 DEG C to continue 20 hours and heat 4 hours at 140 DEG C.It will Precipitating filtering, obtains 4- (the chloro- 4- ethylpyridine -2- of 6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- bis- Base) piperazine -1- t-butyl formate (44mg).LCMS m/z=525.1 [M+H]+。
Step 2:2- ((3,5- bis- chloro- 4- ethyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides
By 4- (the chloro- 4- ethylpyridine -2- base of 6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- two) piperazine Piperazine -1- t-butyl formate (43mg, 0.082mmol) is dissolved in methylene chloride (3mL) and TFA (0.4mL, 5.19mmol) is added.It will The mixture is stirred at room temperature 60 minutes, is then concentrated by blasting air into the mixture and uses alkalinity gilson HPLC (20-80% water contains 0.1%NH for purifying4OH/ acetonitrile).Required fraction is concentrated and is lyophilized, 2- ((3,5- bis- chloro- 4- second are obtained Base -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides (22mg, 0.051mmol, 63% yield).LCMS m/ Z=425.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.85 (s, 1H) 7.47-7.59 (m, 2H) 7.22-7.40 (m, 4H) 5.50 (s, 1H) 3.08-3.22 (m, 4H) 2.74-2.88 (m, 6H) 1.09 (t, J=7.48Hz, 3H).1 proton is not It measures.
Embodiment 328
(1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperazine Pyridine -4- base) t-butyl carbamate
At -20 DEG C, (conjunction is described in embodiment 3, step 2 to chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- Be added in the suspension in ethyl alcohol (2mL) at 300mg, 1.327mmol) piperidin-4-yl t-butyl carbamate (292mg, 1.460mmol) the solution in ethyl alcohol (2.5mL).Then the reaction mixture is stirred 30 minutes at -20 DEG C, is then warmed To 0 DEG C, then by thioacetic acid potassium (227mg, 1.991mmol) and Et3N (0.462mL, 3.32mmol) is together with additional ethyl alcohol (5mL) adds to the reaction mixture.Then the heterogeneous reaction mixture is warmed to 20 DEG C and is stirred overnight mutually synthermal. Methanesulfonic acid 2- amino -2- oxo -1- phenylethylester is added into the reaction mixture (to describe in embodiment 3, step 5 Synthesis, 608mg, 2.65mmol).The reaction is continued to stirring 2.5 hours at 20 DEG C, the reaction temperature is then risen to 40 DEG C simultaneously The reaction is stirred 2.5 hours at 40 DEG C.Inhomogeneous charge object is cooled to room temperature and is filtered.By solid EtOH, water, EtOH, then Et2O washing.Then separated material is dry in vacuum drying oven, obtain (1- (6- ((2- amino -2- oxygen Generation -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl) t-butyl carbamate (520mg).LCMS m/z=521.4 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.96 (s, 1H), 7.47-7.57 (m, 2H), 7.29-7.43 (m, 4H), 6.96 (d, J=7.86Hz, 1H), 5.54 (s, 1H), 4.45 (d, J=10.65Hz, 2H), (3.61 br.s., 1H), 3.21-3.32 (m, 2H), 2.75 (q, J=7.60Hz, 2H), 1.88 (d, J=10.39Hz, 2H), 1.43-1.49 (m, 2H), 1.41 (s, 9H), 1.20 (t, J=7.60Hz, 3H).
Embodiment 329:
N- (4- (((3,5- dicyano -4- ethyl -6- (3- oxypiperazin -1- base) pyridine -2- base) sulfenyl) methyl) benzyl Base) acetamide
The chloro- 4- ethyl -6- of step 1:2- (3- oxypiperazin -1- base) pyridine -3,5- dimethoxy nitrile:
At 0 DEG C, to chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (in 3 step 2 of embodiment describe synthesis, 700mg, 3.10mmol) in the solution in methylene chloride (30mL) be added triethylamine (0.432mL, 3.10mmol), then plus Enter piperazine -2- ketone (310mg, 3.10mmol).The reaction mixture is stirred 3 hours at 25 DEG C.By the reaction mixture ice Cold water (100mL) is quenched and is extracted with DCM (2x 100mL).Combined organic layer is washed with water (2x 100mL) and with anhydrous Sodium sulphate is dried, filtered and is concentrated in vacuo, and obtains 2- chloro- 6- (dimethylamino) -4- ethylpyridine -3,5- dimethoxy nitrile (800mg) is semisolid.LCMS m/z=287.9 [M-H]-。
Step 2:N- (4- (((3,5- dicyano -4- ethyl -6- (3- oxypiperazin -1- base) pyridine -2- base) sulfenyl) first Base) benzyl) acetamide
To the chloro- 4- ethyl -6- of 2- (3- oxypiperazin -1- base) pyridine -3,5- dimethoxy nitrile (250mg) in N, N- dimethyl Thioacetic acid potassium (181mg, 1.584mmol) is added in solution in formamide (5mL) and that the mixture is stirred at room temperature 2 is small When.Potassium carbonate (219mg, 1.584mmol) and N- (4- (bromomethyl) benzyl) acetamide (652mg) is added and by the reaction in room Temperature stirring 1 hour.Water (50mL) is added in the reaction mixture and is extracted with ethyl acetate (2x 30mL).By having for merging Machine layer is dried, filtered with anhydrous sodium sulfate and is concentrated in vacuo to dry.The crude material is passed through into silica gel chromatography (100- 200 mesh are eluted with the DCM solution of 3-4% methanol), obtain N- (4- (((3,5- dicyano -4- ethyl -6- (3- oxypiperazins - 1- yl) pyridine -2- base) sulfenyl) methyl) benzyl) acetamide (230mg, 63% yield) is pale solid.LCMS m/z =449.1 [M+H]+。1H NMR (400MHz, DMSO-d6): δ ppm 8.28 (t, J=6.0Hz, 1H), 8.23 (s, 1H), 7.36 (d, J=8.11Hz, 2H), 7.21 (d, J=8.33Hz, 2H), 4.50 (s, 2H), 4.36 (s, 2H), 4.21 (d, J=5.70Hz, 2H), 4.06-3.96 (m, 2H), 3.33-3.30 (m, 2H), 2.79 (q, J=7.53Hz, 2H), 1.86 (s, 3H), 1.31-1.16 (m, 3H).
Embodiment 330:
2- ((6- (3- (2- amino -2- oxoethyl) azetidine -1- base) -3,5- dicyano -4- ethylpyridine - 2- yl) sulfenyl) -2- phenyl-acetamides
Step 1:2- (azetidine -3- base) acetamide hydrochloride
At 0 DEG C, disliked to 3- (2- amino -2- oxoethyl) azetidine -1- t-butyl formate (2.6g) in Isosorbide-5-Nitrae-two HCl (4M in Isosorbide-5-Nitrae-dioxanes, 5mL, 20.00mmol) is added in solution in alkane (12mL) and by the reaction mixture in room Temperature stirring 4 hours.The mixture is concentrated under reduced pressure, surplus material is ground with ether (20mL), filters and dry, obtains 2- (azetidine -3- base) acetamide hydrochloride (600mg), is pale solid.1H NMR (400MHz, DMSO-d6): δ Ppm 8.15 (s, 4H), 4.41-4.32 (m, 1H), 4.15-4.06 (m, 1H), 4.02-3.90 (m, 1H), 3.86-3.74 (m, 1H), 2.71-2.62 (m, 1H), 2.51-2.41 (m, 2H).
Step 2:2- (1- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) azetidine -3- base) acetamide
At 0 DEG C, to chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (in 3 step 2 of embodiment describe synthesis, 800mg) in the solution in tetrahydrofuran (10mL) be added 2- (azetidine -3- base) acetamide hydrochloride (505mg) and Then sodium bicarbonate aqueous solution (282mg, 3.35mmol) is added in water (10mL).It is small that the reaction mixture is stirred at room temperature 16 When.The reaction mixture is concentrated under reduced pressure, diluted with water (50mL) and is extracted with EtOAc (2x 120mL).By merging Organic layer anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure.By the crude material by silica gel chromatography (60-120 mesh, Eluted with 100%EtOAc), obtain 2- (1- (chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-) azetidine -3- base) Acetamide (280mg), is pale solid.LCMS m/z=304.1 [M+H]+。
Step 3:2- ((6- (3- (2- amino -2- oxoethyl) azetidine -1- base) -3,5- dicyano -4- ethyl Pyridine -2- base) sulfenyl) -2- phenyl-acetamides
In room temperature, to 2- (1- (chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-) azetidine -3- base) acetyl Thioacetic acid potassium (146mg, 1.281mmol) is added in the solution in n,N-Dimethylformamide (6mL) and will for amine (250mg) The reaction mixture was in mutually synthermal stirring 2 hours.Then potassium carbonate (133mg, 0.960mmol) is added, 2- ammonia is then added Base -2- oxo -1- phenylethyl methanesulfonates (describing synthesis, 177mg in 3 step 5 of embodiment) simultaneously mixes the reaction Object is stirred at room temperature 14 hours.The reaction mixture is quenched in cold water (50mL) and is extracted with EtOAc (2x 50mL).It will Combined organic layer anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure, obtain the crude compound.The thick material is passed through into silicon Rubber column gel column chromatogram purification (100-200 mesh is eluted with solution of the 5%MeOH in DCM), obtains 2- ((6- (3- (2- amino -2- oxygen For ethyl) azetidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides (170mg), It is dark brown solid.The brown solid is dissolved in 10%MeOH in the solution in DCM (50mL) and charcoal is added (500mg).Gained mixture is heated 5 minutes at 50 DEG C, is passed throughPad filters and with 10%MeOH at DCM (30mL) In solution washing.The filtrate is concentrated under reduced pressure, 2- ((6- (3- (2- amino -2- oxoethyl) azetidine-is obtained 1- yl) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides (140mg) are pale solid. LCMS m/z=435.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm7.87 (s, 1H), 7.53-7.48 (m, 2H), 7.40-7.27 (m, 4H), 7.24 (s, 1H), 6.86 (br s, 1H), 5.56 (s, 1H), 4.54 (br s, 2H), 4.12 (br s, 2H), 3.06-2.96 (m, 1H), 2.68 (q, J=7.67Hz, 2H), 2.56-2.51 (m, 2H), 1.17 (t, J=7.56Hz, 3H)。
Embodiment 331:
N- (4- (((3,5- dicyano -4- ethyl -6- (3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) methyl) Benzyl) acetamide
At 25 DEG C, to the chloro- 4- ethyl -6- of 2- (3- hydroxyl pyrrolidine -1- base) pyridine -3,5- dimethoxy nitrile (in embodiment 370, synthesis, 250mg are described in step 1) thioacetic acid potassium is added in the solution in n,N-Dimethylformamide (10mL) (100mg, 0.880mmol).By the reaction mixture it is mutually synthermal stirring 2 hours, then be added potassium carbonate (122mg, 0.880mmol), N- (4- (bromomethyl) benzyl) acetamide (577mg) is then added.The reaction mixture is stirred 4 at 25 DEG C Hour.The reaction mixture is quenched with cold water (50mL) and is extracted with EtOAc (2x 150mL).Combined organic layer is used Na2SO4It dries, filters and is concentrated under reduced pressure.By the crude material, by silica gel chromatography, (100-200 mesh, is existed with 5%MeOH Solution elution in DCM), obtain brown solid.The brown solid is dissolved in 10%MeOH in the solution in DCM (50mL), Charcoal (500mg) is added and heats gained mixture 5 minutes at 50 DEG C.The mixture is passed throughPad filtering, is used Solution of the 10%MeOH in DCM (40mL) washs and the filtrate decompression is concentrated, and obtains N- (4- (((3,5- dicyano -4- second Base -6- (3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) methyl) benzyl) acetamide (162mg), it is solid for canescence Body.LCMS m/z=436.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.30 (t, J=6.0Hz, 1H), 7.35 (d, J=8.1Hz, 2H), 7.20 (d, J=8.1Hz, 2H), 5.11 (d, J=3.6Hz, 1H), 4.49 (s, 2H), 4.42-4.37 (m, 1H), 4.21 (d, J=5.9Hz, 2H), 3.93-3.83 (m, 3H), 3.77-3.69 (m, 1H), 2.76 (q, J=7.6Hz, 2H), 1.99-1.91 (m, 2H), 1.85 (s, 3H), 1.21 (t, J=7.6Hz, 3H).
Embodiment 332
N- (4- (1- (3,5- dicyano -6- (4- (dimethylamino) piperidin-1-yl) -4- ethylpyridine -2- base sulfenyl) Propyl) benzyl) acetamide, trifluoroacetate
Step 1:1- (4- (amino methyl) phenyl) propyl- 1- alcohol
At 0 DEG C, LAH is added in the solution in THF (150mL) to 4- propiono benzonitrile (3.6g, 22.62mmol) (1.717g, 45.2mmol).Gained mixture is stirred at room temperature overnight, water is subsequently poured into.By the mixture ethyl acetate (500mL) is extracted and is washed organic phase water (250mL), salt water (250mL), dry with sodium sulphate, is evaporated, is obtained under reduced pressure To title compound 1- (4- (amino methyl) phenyl) propyl- 1- alcohol (3.6g).LCMS m/z=166.2 [M+H]+。
Step 2:N- (4- (1- (3,5- dicyano -6- (4- (dimethylamino) piperidin-1-yl) -4- ethylpyridine -2- Base sulfenyl) propyl) benzyl) acetamide, trifluoroacetate
In room temperature, to 1- (4- (amino methyl) phenyl) propyl- 1- alcohol (3.6g, 21.79mmol) in N, N- dimethyl formyl Acetic anhydride (8.90g, 87mmol) is added in solution in amine (50mL).The mixture is stirred at room temperature overnight.Gained is mixed It closes object to be diluted with ethyl acetate (50mL), be washed with water (25mL) and salt water (25mL), steamed with sodium sulphate drying and under reduced pressure Hair.Toluene (50mL) and lawesson reagent (1.951g, 4.82mmol) are added into the residue.The mixture is stirred at 110 DEG C It mixes overnight.Gained mixture is cooling, it evaporates under reduced pressure, obtains the crude product, it (is used into petroleum with silica gel chromatography Ether/ethyl acetate=2:1 elution), obtain residue.In room temperature, to the chloro- 6- of 2- (4- (dimethylamino) piperidin-1-yl) -4- Ethylpyridine -3,5- dimethoxy nitrile (1.423g, 4.48mmol) and potassium carbonate (1.238g, 8.96mmol) are in N, N- dimethyl formyl Above-mentioned residue is added in solution in amine (50mL).The mixture is stirred at room temperature overnight.By mixture acetic acid second Ester (60mL) dilution, is washed with water (30mL) and saturated brine (30mL).By organic phase anhydrous sodium sulfate drying and depressurize Concentration.Thick material residue preparative-HPLC is purified, N- (4- (1- ((3,5- dicyano -6- (4- (dimethyl are obtained Amino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) propyl) benzyl) acetamide, trifluoroacetate (6mg).LCMS m/ Z=505.2 [M+H]+。1H NMR (400MHz, CDCl3) δ ppm 12.28 (s, 1H), 7.36 (d, J=7.9Hz, 2H), 7.25 (t, J=6.1Hz, 2H), 6.87 (s, 1H), 6.01-5.55 (m, 2H), 4.80-4.63 (m, 2H), 4.55 (d, J=12.3Hz, 1H), 4.43 (dt, J=15.4,7.2Hz, 2H), 3.47 (s, 1H), 3.07 (t, J=12.6Hz, 1H), 2.97-2.92 (m, 1H), 2.86 (d, J=11.3Hz, 3H), 2.77 (s, 3H), 2.15-2.02 (m, 6H), 1.76 (tdd, J=20.6,13.0, 7.6Hz, 1H), 1.49 (dd, J=21.3,12.8Hz, 1H), 1.32 (t, J=7.6Hz, 3H), 0.99 (t, J=7.3Hz, 3H), 0.90 (t, J=7.4Hz, 1H).
Embodiment 333:
(2R) -2- amino -3 Methylbutanoic acid 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyan Base -4- ethylpyridine -2- base) azetidine -3- base ester
Step 1:(2S) -2- ((tertbutyloxycarbonyl) amino) -3 Methylbutanoic acid 1- (6- ((2- amino -2- oxo -1- benzene Base ethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) azetidine -3- base ester
To 2,4,6- trichloro-benzoyl chlorides (231mg, 0.945mmol) and (S) -2- ((tertbutyloxycarbonyl) amino) -3- first Base butyric acid (437mg, 1.891mmol) is added in the solution in n,N-Dimethylformamide (2mL) and tetrahydrofuran (20mL) Triethylamine (0.132mL, 0.945mmol) simultaneously stirs the mixture 5 hours at 0 DEG C.Then, in 0 DEG C of addition 2- ((3,5- bis- Cyano -4- ethyl -6- (3- hydroxy azetidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides are (in embodiment 146, synthesis, 400mg, 0.945mmol are described in step 2) and DMAP (116mg, 0.945mmol).By the reaction mixture It is stirred at room temperature 1 hour.The reaction mixture is quenched with ice cold water (50mL) and is extracted with ethyl acetate (2x 100mL).It will Combined organic layer anhydrous Na2SO4It is dried, filtered and concentrated.The crude material is passed through into silica gel chromatography (100-200 Mesh, with the hexanes of 20% ethyl acetate), obtain (2S) -2- ((tertbutyloxycarbonyl) amino) -3 Methylbutanoic acid 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) azetidine -3- Base ester (250mg), is brown solid.LCMS m/z=593.4 [M+H]+。
Step 2:(2R) -2- amino -3 Methylbutanoic acid 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3, 5- dicyano -4- ethylpyridine -2- base) azetidine -3- base ester
At 0 DEG C, to (2S) -2- ((tertbutyloxycarbonyl) amino) -3 Methylbutanoic acid 1- (6- ((2- amino -2- oxo -1- Phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) and azetidine -3- base ester (250mg) 1,4- bis- dislike HCl (Isosorbide-5-Nitrae-dioxane of 4M, 2mL, 8.00mmol) is added in solution in alkane (2mL).By the reaction mixture in room Temperature stirring 45 minutes.The reaction mixture is concentrated under reduced pressure, raw product is obtained, it is purified with preparative-SFC, is obtained To (2R) -2- amino -3 Methylbutanoic acid 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- second Yl pyridines -2- base) azetidine -3- base ester (20mg).LCMS m/z=493.1 [M+H]+。1H NMR (400MHz, DMSO- d6) δ ppm 7.86 (br s, 1H), 7.51 (br d, J=7.23Hz, 2H), 7.41-7.23 (m, 4H), 5.57 (s, 1H), 5.29 (br s, 1H), 4.80 (br s, 2H), 4.36 (br s, 2H), 3.23-3.19 (m, 1H), 2.70 (q, J=7.53Hz, 2H), 1.92 (br d, J=6.58Hz, 3H), 1.24 (br s, 1H), 1.18 (br t, J=7.56Hz, 3H), 0.82-0.97 (m, 6H)。
Embodiment 335
N- (5- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) pyridine -2- base) methylsulfonamides
At 0 DEG C, to 2- (((6- aminopyridine -3- base) methyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- diaza Cycloheptane -1- base) pyridine -3,5- dimethoxy nitrile (synthesis, 60mg, 0.147mmol are described in embodiment 300) is at THF (2mL) In solution in mesyl chloride (0.025mL, 0.321mmol) solution in THF (0.5mL) is added dropwise, TEA is then added dropwise (0.062mL, 0.442mmol).By the reaction mixture stir 30 minutes, then by more mesyl chlorides (0.008mL, It 0.102mmol) adds in the solution.The reaction mixture is concentrated and purified with RP-HPLC (20-60% acetonitrile/water, 0.1% NH4The aqueous solution of OH), obtain N- (5- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) Pyridine -2- base) sulfenyl) methyl) pyridine -2- base) methylsulfonamides (16mg, 0.033mmol, 22% yield), it is solid for white Body.LCMS m/z=486.3 [M+H]+.1H NMR (400MHz, DMSO-d6) δ ppm 1.22 (t, J=7.6Hz, 3H), 1.87- 1.97 (m, 2H), 2.24 (s, 3H), 2.47 (br.s., 2H), 2.59-2.70 (m, 2H), 2.78 (q, J=7.6Hz, 2H), 3.26 (s, 3H), 3.82-3.97 (m, 4H), 4.46 (s, 2H), 6.94 (d, J=8.6Hz, 1H), 7.75 (dd, J=8.6,2.5Hz, 1H), 8.26 (d, J=2.0Hz, 1H), 10.79 (br.s., 1H).
Embodiment 336:
2- (6- (4- (acetylamino methyl) benzyl sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base sulfenyl) -2- benzene Yl acetamide
Step 1:(4- (amino methyl) phenyl) methanol
To suspension of the lithium aluminium hydride reduction (7.07g, 186mmol) stirred in 0 DEG C of air in tetrahydrofuran (400mL) The solution of 4- cyano-benzoic acid methyl ester (10g, 62.1mmol) in tetrahydrofuran (400mL) is added dropwise in liquid, continues 15 minutes.It will The reaction mixture stirs 15 hours at 50 DEG C, is subsequently cooled to 0 DEG C and by being slowly added to water (7mL), 15%NaOH (7mL) It is quenched with water (21mL).Gained precipitating is stirred for 30 minutes and is filtered.The filter vacuum is concentrated, (4- (amino first is obtained Base) phenyl) methanol (6.8g, 80% yield) is light yellow oil.LCMS m/z=138.0 [M+H]+。
Step 2:N- (4- (hydroxymethyl) benzyl) acetamide
To (4- (amino methyl) phenyl) methanol (6.8g, 49.6mmol) and triethylamine stirred in 0 DEG C of air Acetic anhydride (5.57g, 54.5mmol) is added dropwise in dichloro in (20.73mL, 149mmol) in the solution in methylene chloride (150mL) Solution in methane (150mL) continues 5 minutes.The reaction mixture is stirred 12 hours at 25 DEG C.The reaction mixture is dense Contracting, by the residue purification by flash chromatography, obtains N- (4- (hydroxymethyl) benzyl) acetamide (6.5g, 73% yield), For white solid.LCMS m/z=180.0 [M+H]+。
Step 3:N- (4- (chloromethyl) benzyl) acetamide
To N- (4- (hydroxymethyl) benzyl) acetamide (6.5g, 36.3mmol) and triethylamine stirred in 0 DEG C of air Methane sulfonyl chloride (4.15g, 36.3mmol) is added dropwise two in (7.58mL, 54.4mmol) in the solution in methylene chloride (15mL) Solution in chloromethanes (15mL) continues 5 minutes.The reaction mixture is stirred 12 hours at 25 DEG C.By the reaction mixture Concentration, which is purified and (is eluted with MeOH-DCM=0-2.5%) with column chromatography, obtain N- (4- (chloromethyl) benzyl) second Amide (5.3g), is white solid.LCMS m/z=198.1 [M+H]+。
Step 4: thioacetic acid S-4- (acetylamino methyl) benzyl ester
To N- (4- (chloromethyl) benzyl) acetamide (2.96g, 14.98mmol) stirred in air at room temperature in N, N- Thioacetic acid potassium (1.88g, 16.47mmol) is added in solution in dimethylformamide (40mL).The reaction mixture is existed 25 DEG C are stirred 0.5 hour.The reaction mixture is concentrated, by the residue flash column chromatography, obtains thioacetic acid S- 4- (acetylamino methyl) benzyl ester (3.4g, 96%), is white solid.LCMS m/z=238.0 [M+H]+。
Step 5: pyridine -1- (E) -1,1- dicyano -2- (cyano (isocyano group) methylene) butyl- 1- anion
To malononitrile (25g, 378mmol) and 1,1,1- triethoxybutane (40g, 210mmol) is in pyridine (16mL) Solution stirred in 20 DEG C of air.The reaction mixture is stirred 1 hour at 120 DEG C.The mixture is concentrated, is added EtOAc simultaneously filters the solid, obtains pyridine -1- (E) -1,1- dicyano -2- (cyano (isocyano group) methylene) butyl- 1- yin Ion (Pyridin-1-ium (E) -1,1-dicyano-2- (cyano (isocyano) methylene) butan-1-ide) (10g, 19%) is used in next step without is further purified1H NMR (400MHz, DMSO) δ ppm 8.93 (d, J= 5.1Hz, 2H), 8.62-8.54 (m, 1H), 8.06 (dd, J=7.7,6.6Hz, 1H), 2.33 (q, J=7.5Hz, 2H), 1.09 (t, J=7.6Hz, 3H).
The chloro- 4- ethylpyridine -3,5- dimethoxy nitrile of step 6:2- amino -6-
By concentrated hydrochloric acid (67.0mL) and pyridine -1- (E) -1,1- dicyano -2- (cyano (isocyano group) methylene) butyl- Solution of the 1- anion (10g, 40.1mmol) in acetone (100mL) stirs 16 hours at 50 DEG C.By the dark brown mixture Cooling simultaneously filters the solid of precipitation, obtains chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2- amino -6- (7g, 84%).LCMS m/ Z=205.2 [M-H]-。
Step 7:N- (4- ((6- amino -3,5- dicyano -4- ethylpyridine -2- base sulfenyl) methyl) benzyl) acetamide
To thioacetic acid S-4- (acetylamino methyl) benzyl ester (3.4g, 14.33mmol) stirred in 0 DEG C of air The solution of sodium methoxide (0.77g, 14.33mmol) in methanol (30mL) is added in the solution in methanol (30mL).By the reaction Mixture stirs 2 hours at 0 DEG C.The reaction mixture is concentrated to get residue, is dissolved in n,N-Dimethylformamide (15mL).Chloro- 4- ethylpyridine -3,5- dimethoxy nitrile (2.96g, the 14.33mmol) He Sanyi of 2- amino -6- is added into the solution Amine (3.99mL, 28.7mmol).The reaction mixture is stirred 12 hours at 25 DEG C.The reaction mixture is evaporated and this is residual Excess is allocated between methylene chloride (100mL) and water (50mL).The organic phase is washed with salt water (25mL), it is dry with sodium sulphate Dry, filtering and vacuum evaporation obtain raw product, are yellow solid, it is used purification by flash chromatography, obtains N- (4- ((6- Amino -3,5- dicyano -4- ethylpyridine -2- base sulfenyl) methyl) benzyl) acetamide (3.4g, 96%) is white solid. LCMS m/z=365.8 [M+H]+。
Step 8:N- (4- ((the chloro- 3,5- dicyano -4- ethylpyridine -2- base sulfenyl of 6-) methyl) benzyl) acetamide
To the copper chloride (II) (806mg, 6mmol) stirred at 0 DEG C in CH3Nitrous is added in solution in-CN (10mL) Tert-butyl acrylate (618mg, 6mmol) is in CH3In solution in-CN (10mL).Gained mixture is stirred 0.5 hour at 0 DEG C.To N- (4- ((6- amino -3,5- dicyano -4- ethylpyridine -2- base sulfenyl) methyl) benzyl) acetamide is added in the mixture The solution of (730mg, 2mmol).The reaction mixture is stirred 2 hours at 60 DEG C.It is after concentration, raw product column chromatography is pure Change, obtain N- (4- ((chloro- 3, the 5- dicyano -4- ethylpyridine -2- base sulfenyl of 6-) methyl) benzyl) acetamide (345mg, 45% Yield), it is light yellow solid.LCMS m/z=384.8 [M+H]+。
Step 9:2- (6- (4- (acetylamino methyl) benzyl sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base sulphur Base) -2- phenyl-acetamides
To thioacetic acid S- (2- amino -2- oxo -1- phenylethyl) ester stirred in 0 DEG C of air (in embodiment 62, step 5, in describe synthesis 188mg, 0.90mmol) in the solution in methanol (10mL) be added sodium methoxide solution (33wt% in methyl alcohol, 0.15mL, 0.90mmol).The reaction mixture is stirred 2 hours at 0 DEG C.After concentration, by the remnants Object DMF is dissolved in and N- (4- (((the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) sulfenyl) methyl) is added into the mixture Benzyl) acetamide (345mg, 0.90mmol) and triethylamine (0.25mL, 1.79mmol).The reaction mixture is stirred at 25 DEG C 12 hours.By the reaction mixture be allocated between EtOAc (50mL) and water (15mL) and by organic phase water (15mL x 2), Salt water (15mL) washing, uses Na2SO4It is dried, filtered and concentrated.By the thick material flash column chromatography, 2- (6- (4- is obtained (acetylamino methyl) benzyl sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base sulfenyl) -2- phenyl-acetamides (105mg, It 22%), is white solid.LCMS m/z=515.8 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.37 (t, J= 5.9Hz, 1H), 8.04 (s, 1H), 7.54 (d, J=6.7Hz, 2H), 7.47 (s, 1H), 7.42-7.35 (m, 5H), 7.26 (d, J =8.0Hz, 2H), 5.80 (s, 1H), 4.67-4.55 (m, 2H), 4.25 (d, J=5.9Hz, 2H), 2.81 (q, J=7.5Hz, 2H), 1.87 (s, 3H), 1.23 (t, J=7.6Hz, 3H).
Embodiment 337:
4- ethyl -2- ((4- (pyridin-3-yl) benzyl) sulfenyl) -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine - 3,5- dimethoxy nitrile
Step 1:4- (pyrrolidin-1-yl) piperidines -1- t-butyl formate
By 4- oxo-piperidine -1- t-butyl formate (5.49g, 27.5mmol) and pyrrolidines (1.78g, 25.03mmol) and Sodium triacetoxy borohydride (10.61g, 50.1mmol) stirs 18 in 20 DEG C of air in the solution in methylene chloride (30mL) Hour.The mixture is concentrated, residue flash column chromatography (is eluted) with MeOH-DCM 0-5%, obtains 4- (pyrrolidin-1-yl) piperidines -1- t-butyl formate (3.1g, 49%) is faint yellow oil.LCMS m/z=255.0 [M+H]+。
Step 2:4- (pyrrolidin-1-yl) piperidines
It is molten in methanol (20mL) to 4- (pyrrolidin-1-yl) piperidines -1- t-butyl formate (3.1g, 12.19mmol) Solution (5mL, 33%) of the hydrochloride in MeOH is added in liquid.The reaction mixture is stirred 3 hours at 20 DEG C, is then concentrated Obtain 4- (pyrrolidin-1-yl) piperidines, 2 hydrochlorides (3g).LCMS m/z=155.2 [M+H]+。
The chloro- 4- ethyl -6- of step 3:2- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -3,5- dimethoxy nitrile
To 4- two-HCl salt of (pyrrolidin-1-yl) piperidines (3g, 13.21mmol) and 2, chloro- ethylpyridine -3 4- 6- bis-, 5- dimethoxy nitrile (describing synthesis, 2.99g, 13.21mmol in 3 step 2 of embodiment) is at n,N-Dimethylformamide (20mL) In solution in be added dropwise triethylamine (4.01g, 39.6mmol).The reaction mixture is stirred 18 hours at 20 DEG C.By the mixing Object is concentrated and uses flash column chromatography (being eluted with MeOH-DCM 0-1%), obtains the chloro- 4- ethyl -6- (4- (pyrrolidines-of 2- 1- yl) piperidin-1-yl) pyridine -3,5- dimethoxy nitrile (3g, 66%) is yellow solid.LCMS m/z=343.6 [M+H]+。
Step 4:2- ((4- bromobenzyl) sulfenyl) -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -3, 5- dimethoxy nitrile
By the chloro- 4- ethyl -6- of 2- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -3,5- dimethoxy nitrile (3g, 8.72mmol), triethylamine (1.324g, 13.09mmol) and (4- bromophenyl) methyl mercaptan (1.95g, 9.60mmol) are in N, N- bis- Solution in methylformamide (20mL) stirs 18 hours at 20 DEG C, is then concentrated.By the residue flash column chromatography (being eluted with MeOH-DCM 0-1%), obtains 2- ((4- bromobenzyl) sulfenyl) -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidines - 1- yl) pyridine -3,5- dimethoxy nitrile, be yellow solid (2.5g, 56%).LCMS m/z=509.8 [M+H]+。
Step 5:4- ethyl -2- ((4- (pyridin-3-yl) benzyl) sulfenyl) -6- (4- (pyrrolidin-1-yl) piperidines -1- Base) pyridine -3,5- dimethoxy nitrile
At 20 DEG C, to 1,1'- bis- (diphenylphosphine) ferrocene palladium chloride (II) dichloromethane complex (71mg, 0.01mmol), pyridin-3-yl boric acid (58mg, 0.47mmol) and 2- ((4- bromobenzyl) sulfenyl) -4- ethyl -6- (4- (pyrroles Alkane -1- base) piperidin-1-yl) pyridine -3,5- dimethoxy nitrile (500mg, 0.98mmol) is in the solution in Isosorbide-5-Nitrae-dioxanes (10mL) The solution of sodium carbonate (156mg, 1.47mmol) in water (2mL) is added.The mixture is stirred 18 hours at 100 DEG C.It should Mixture is concentrated in vacuo and uses silica gel column purification, obtains 4- ethyl -2- ((4- (pyridin-3-yl) benzyl) sulfenyl) -6- (4- (pyrrole Cough up alkane -1- base) piperidin-1-yl) pyridine -3,5- dimethoxy nitrile (117mg, 23%) is light yellow solid.LCMS m/z= 508.9[M+H]+。1H NMR (400MHz, CDCl3) δ ppm8.83 (s, 1H), 8.60 (d, J=4.6Hz, 1H), 7.87 (d, J= 7.9Hz, 1H), 7.56 (d, J=8.2Hz, 2H), 7.48 (d, J=8.2Hz, 2H), 7.37 (dd, J=7.9,4.8Hz, 1H), 4.61 (d, J=13.2Hz, 2H), 4.46 (s, 2H), 3.20 (t, J=12.4Hz, 2H), 2.92 (q, J=7.6Hz, 2H), 2.85-2.45 (m, 4H), 2.20-1.67 (m, 9H), 1.33 (t, J=7.6Hz, 3H).
Embodiment 338:
4- ethyl -2- ((4- (pyridin-4-yl) benzyl) sulfenyl) -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine - 3,5- dimethoxy nitrile
At 20 DEG C, to 1,1'- bis- (diphenylphosphine) ferrocene palladium chloride (II) dichloromethane complex (50mg, 0.07mmol), pyridin-4-yl boric acid (101mg, 0.82mmol) and 2- ((4- bromobenzyl) sulfenyl) -4- ethyl -6- (4- (pyrroles Alkane -1- base) piperidin-1-yl) pyridine -3,5- dimethoxy nitrile (describe synthesis in 337 step 4 of embodiment, 350mg, Sodium carbonate (109mg, 1.03mmol) 0.69mmol) is added in the solution in Isosorbide-5-Nitrae-dioxanes (10mL) in water (2mL) Solution.The mixture is stirred 18 hours at 100 DEG C.The mixture is concentrated in vacuo to and is used silica gel column purification, obtains 4- ethyl- 2- ((4- (pyridin-4-yl) benzyl) sulfenyl) -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -3,5- dimethoxy nitrile (118mg, 33%), is light yellow solid.LCMS m/z=508.9 [M+H]+。1H NMR (400MHz, CDCl3)δppm 8.66 (dd, J=4.6,1.5Hz, 2H), 7.62 (d, J=8.2Hz, 2H), 7.54-7.45 (m, 4H), 4.62 (d, J= 12.0Hz, 2H), 4.46 (s, 2H), 3.18 (t, J=12.6Hz, 2H), 2.99-2.50 (m, 6H), 2.18-1.70 (m, 9H), 1.33 (t, J=7.6Hz, 2H).
Embodiment 339:
2- amino-N- (1- (3,5- dicyano -4- ethyl -6- ((4- sulfamoylbenzyl) sulfenyl) pyridine -2- base) piperazine Pyridine -4- base) acetamide hydrochloride
Step 1:2- (4- amino piperidine -1- base) chloro- 4- ethylpyridine -3,5- dimethoxy nitrile of -6-, hydrochloride
In room temperature, to (1- (chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-) piperidin-4-yl) the tertiary fourth of carbamic acid Ester (synthesis, 1.5g, 3.57mmol are described in embodiment 81, step 1) is added in the solution in Isosorbide-5-Nitrae-dioxanes (5mL) The Isosorbide-5-Nitrae dioxane (12mL, 48.0mmol) of 4M HCl simultaneously stirs 4 hours.The reaction mixture is concentrated completely, this is residual Excess is washed with ether (2x30mL), obtains 2- (4- amino piperidine -1- base) chloro- 4- ethylpyridine -3,5- dimethoxy nitrile of -6-, salt Hydrochlorate (1.03g, 3.12mmol, 87% yield), is pale solid.LCMS m/z=290.1 [M+H]+。
Step 2:(2- ((1- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) piperidin-4-yl) amino) -2- oxo Ethyl) t-butyl carbamate
In room temperature, to 2- (4- amino piperidine -1- base) chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of -6-, hydrochloride (1g, HATU (1.748g, 4.60mmol), diisopropyl 3.07mmol) are added in the solution in n,N-Dimethylformamide (15mL) Ethamine (1.071mL, 6.13mmol) and 2- ((tertbutyloxycarbonyl) amino) acetic acid (0.537g, 3.07mmol) simultaneously mix the reaction Object is closed to be stirred at room temperature 16 hours.The reaction mixture is diluted with water (20mL) and is extracted with ethyl acetate (2x 20mL).It will Organic layer concentration, obtains (2- ((1- (chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-) piperidin-4-yl) amino) -2- oxo Ethyl) t-butyl carbamate (1.7g) is pale solid.LCMS m/z=447.1 [M+H]+。
Step 3:(2- ((1- (3,5- dicyano -4- ethyl -6- ((4- sulfamoylbenzyl) sulfenyl) pyridine -2- base) piperazine Pyridine -4- base) amino) -2- oxoethyl) t-butyl carbamate
In room temperature, to (2- ((1- (chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-) piperidin-4-yl) amino) -2- Oxoethyl) thioacetic acid potassium is added in the solution in N,N-dimethylformamide (5mL) in t-butyl carbamate (0.7g) (0.308g, 2.70mmol).After being stirred at room temperature 2 hours, potassium carbonate (0.372g, 2.70mmol) and 4- (bromomethyl) benzene is added Simultaneously the reaction mixture is stirred at room temperature 16 hours for sulfonamide (0.337g, 1.348mmol).It is added water (20mL) and this is anti- Mixture EtOAc (2x 20mL) is answered to extract.By organic layer anhydrous Na2SO4It dries, filters and is concentrated in vacuo to dry.It should Crude material is obtained by silica gel chromatography (100-200 mesh is eluted with the petroleum ether solution of 30-40% ethyl acetate) (2- ((1- (3,5- dicyano -4- ethyl -6- ((4- sulfamoylbenzyl) sulfenyl) pyridine -2- base) piperidin-4-yl) amino) - 2- oxoethyl) t-butyl carbamate (420mg) is pale solid.LCMS m/z=614.5 [M+H]+。
Step 4:2- amino-N- (1- (3,5- dicyano -4- ethyl -6- ((4- sulfamoylbenzyl) sulfenyl) pyridine -2- Base) piperidin-4-yl) acetamide hydrochloride
Under 20 DEG C of nitrogen, to (2- ((1- (3,5- dicyano -4- ethyl -6- ((4- sulfamoylbenzyl) sulfenyl) pyrrole Pyridine -2- base) piperidin-4-yl) amino) -2- oxoethyl) t-butyl carbamate (0.4g) is in 1,4- dioxanes (5mL) Hydrochloric acid (4M, Isosorbide-5-Nitrae-dioxanes, 0.332mL, 1.328mmol) is added in agitating solution.The reaction mixture is stirred 2 at 25 DEG C Hour.Ether (20mL) is added in the reaction and filters the mixture, obtains 2- amino-N- (1- (3,5- dicyano -4- Ethyl -6- ((4- sulfamoylbenzyl) sulfenyl) pyridine -2- base) piperidin-4-yl) acetamide hydrochloride (0.230g), for ash White solid.LCMS m/z=514.2 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.50 (br s, 1H), 8.05 (br s, 3H), 7.78 (d, J=8.55Hz, 2H), 7.59 (d, J=8.55Hz, 2H), 7.34 (s, 2H), 4.57 (s, 2H), 4.34 (br d, J=13.59Hz, 2H), 3.99 (br s, 1H), 3.54 (br s, 2H), 3.41 (br t, J=11.62Hz, 2H), 2.77 (q, J=7.31Hz, 2H), 1.91 (br d, J=10.74Hz, 2H), 1.48 (q, J=9.72Hz, 2H), 1.22 (t, J=7.56Hz, 3H).
Embodiment 340
2- ((3,5- dicyano -4- ethyl -6- (methyl ((5- oxo -4,5- dihydro -1H-1,2,4- triazole -3- base) first Base) amino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides
Thioacetic acid S- (2- amino -2- oxo -1- phenylethyl) ester (in 62 step 5 of embodiment is described into conjunction At 112mg, 0.535mmol) and NaBH4First reaction mixture of (36.8mg, 0.973mmol) in ethyl alcohol (3mL) is 60 DEG C heating 25 minutes (bubbling stopping), then cool down.To chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (in embodiment 3, step Synthesis, 110mg, 0.487mmol are described in rapid 2) 3- ((methylamino) first is slowly added in the solution in DMF (2.0mL) Base) -1H-1,2,4- triazole -5 (4H) -one, hydrochloride (91mg, 0.535mmol) and TEA (0.136mL, 0.973mmol) exist Pulp solution in DMF (2.5mL).Second reaction mixture is stirred at room temperature 20 minutes.First and second reactions are mixed It closes object to merge, then be stirred overnight.The reaction mixture water (30mL) is diluted and stirred 30 minutes.Simultaneously by solid filtering With RP-HPLC (5-30% acetonitrile/water, 0.1%NH4The aqueous solution of OH) purifying, obtain 2- ((3,5- dicyano -4- ethyl -6- (methyl ((5- oxo -4,5- dihydro -1H-1,2,4- triazole -3- base) methyl) amino) pyridine -2- base) sulfenyl) -2- phenyl second Amide (44mg, 0.098mmol, 20% yield), is white solid.LCMS m/z=449.2 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm1.22 (t, J=7.6Hz, 3H), 2.79 (q, J=7.4Hz, 2H), 3.33 (s, 3H), 4.68 (d, J=16.5Hz, 1H), 5.07 (d, J=16.5Hz, 1H), 5.58 (s, 1H), 7.30-7.40 (m, 4H), 7.44-7.50 (m, 2H), 7.89 (s, 1H), 11.42 (s, 2H).
Embodiment 341
2- ((6- (((4H-1,2,4- triazole -3- base) methyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine - 2- yl) sulfenyl) -2- phenyl-acetamides
Thioacetic acid S- (2- amino -2- oxo -1- phenylethyl) ester (in 62 step 5 of embodiment is described into conjunction At the first reaction mixture of 112mg, 0.535mmol) and NaBH4 (36.8mg, 0.973mmol) in ethyl alcohol (3mL) 60 DEG C heating 25 minutes (bubbling stopping), then cool down.To chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (in embodiment 3, step Synthesis, 110mg, 0.487mmol are described in rapid 2) be slowly added in the solution in DMF (2.0mL) N- methyl-1-(4H-1, 2,4- triazole -3- bases) methylamine, hydrochloride (84mg, 0.535mmol) and TEA (0.136mL, 0.973mmol) are at DMF (2.5mL) In slurry.Second reaction mixture is stirred at room temperature 20 minutes.First and second reaction mixture is merged, is then stirred It mixes 1 hour.The reaction mixture is concentrated and purifies (10-40% acetonitrile/water, 0.1%NH with RP-HPLC4The aqueous solution of OH), Obtain 2- ((6- (((4H-1,2,4- triazole -3- base) methyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) Sulfenyl) -2- phenyl-acetamides (75mg, 0.173mmol, 36% yield) are white solid.LCMS m/z=433.2 [M+H ]+。1H NMR (400MHz, DMSO-d6) δ ppm 1.21 (t, J=7.6Hz, 3H), 2.77 (q, J=7.6Hz, 2H), 3.41 (s, 3H), 4.91 (d, J=16.2Hz, 1H), 5.35 (d, J=16.2Hz, 1H), 5.60 (s, 1H), 7.27-7.40 (m, 5H), 7.42-7.47 (m, 2H), 7.95 (s, 1H), 8.44 (br.s., 1H).
Embodiment 342
2- ((3,5- dicyano -4- ethyoxyl -6- picoline -2- base) sulfenyl) -2- phenyl-acetamides
Step 1:2- amino -4- ethyoxyl -6- picoline -3,5- dimethoxy nitrile
Chloro- 4- ethoxy pyridine -3, the 5- dimethoxy nitrile of 2- amino -6- (synthesis is described in embodiment 192, step 1, 370mg, 1.662mmol), 2,4,6- trimethyls -1,3, the miscellaneous own ring (0.35mL, 2.504mmol) of 5,2,4,6- trioxa, three boron, Cesium carbonate (1820mg, 5.59mmol) and PdCl2(dppf)-CH2Cl2Adduct (127mg, 0.156mmol) adds to microwave vial In and be suspended in 1,4- dioxanes (18mL): water (1.00mL).The mixture is heated 1 hour in 90 DEG C of microwave reactors. Pass throughPad filtering simultaneously extracts the filtrate salt water and EtOAc (3x).Combined organic matter is washed with brine, is used MgSO4It dries, filters and is concentrated, obtain residue.The residue is used into reverse phase Isco chromatogram purification (0- on C18Aq. column 60-70-100%0.1%NH4OH aqueous solution/acetonitrile).Required fraction is merged and is concentrated, 2- amino -4- ethyoxyl -6- is obtained Picoline -3,5- dimethoxy nitrile (95mg, 0.470mmol, 28% yield).LCMS m/z=203.0 [M+H]+。
Step 2:4- ethyoxyl -2- sulfydryl -6- picoline -3,5- dimethoxy nitrile
By 2- amino -4- ethyoxyl -6- picoline -3,5- dimethoxy nitrile (87mg, 0.430mmol) and copper chloride (II) (124mg, 0.922mmol) is suspended in acetonitrile (20mL) and the mixture is heated to 50 DEG C.By nitrite tert-butyl (0.13mL, 0.987mmol) is added dropwise in the mixture of heating and stirs suspension 30 minutes at 60 DEG C.It is cooled to 0 DEG C simultaneously It is diluted with EtOAc and salt water.It is extracted with EtOAc (4x) and is washed with brine combined organic matter, use MgSO4It dries, filters And be concentrated, obtain residue.Be added thioacetic acid potassium (102mg, 0.893mmol) and be suspended in containing TEA (0.070mL, In EtOH (15mL) 0.502mmol).The mixture is heated to 60 DEG C and continues 25 minutes.It filters out unwanted salt and incites somebody to action The filtrate is condensed into residue, it is used reverse phase Isco chromatogram purification (0-65-100%0.1%NH on C18Aq. column4OH Aqueous solution/acetonitrile).Required fraction is merged and is concentrated, crude 4- ethyoxyl -2- sulfydryl -6- picoline -3,5- bis- is obtained Formonitrile HCN (65mg, 78% purity).LCMS m/z=242.4 [M+Na]+。
Step 3:2- ((3,5- dicyano -4- ethyoxyl -6- picoline -2- base) sulfenyl) -2- phenyl-acetamides
By 4- ethyoxyl -2- sulfydryl -6- picoline -3,5- dimethoxy nitrile (65mg, 78% purity), the chloro- 2- phenyl second of 2- Amide (46mg, 0.271mmol) and sodium bicarbonate aqueous solution (95mg, 1.131mmol) are suspended in n,N-Dimethylformamide It is stirred at room temperature 5 hours in (6mL) and by the mixture.Material is fed directly to RP Isco C18 column to be used to purify (0-55- 100%0.1%NH4OH aqueous solution/acetonitrile).Required fraction is merged and is concentrated, 2- ((3,5- dicyano -4- ethyoxyls-are obtained 6- picoline -2- base) sulfenyl) -2- phenyl-acetamides (34mg).LCMS m/z=353.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.94 (s, 1H) 7.52-7.60 (m, 2H) 7.27-7.42 (m, 4H) 5.72 (s, 1H) 4.72 (q, J= 6.84Hz, 2H) 2.65 (s, 3H) 1.39 (t, J=6.97Hz, 3H).
Embodiment 343
2- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) phenyl)-N- (2- hydroxyethyl) acetamide
Step 1:2- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyrrole Pyridine -2- base) sulfenyl) methyl) phenyl) acetic acid
At 0 DEG C, to 4- ethyl -2- sulfydryl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -3,5- diformazan Nitrile (synthesis, 232mg, 0.770mmol are described in embodiment 69, step 1) and Et3N (0.107mL, 0.770mmol) is in chlorine 2- (4- (bromomethyl) phenyl) acetic acid (141mg, 0.616mmol) is added in suspension in imitative (1mL) in chloroform (2.5mL) Solution.Then the reaction mixture is stirred overnight at 0 DEG C.After 0 DEG C is stirred overnight, which is warmed to room Temperature.The reaction mixture is filtered.The filtrate is concentrated.The thick material reversed-phase HPLC is purified into (Gilson, 30mm x 50mm Gemini column, NH4OH modifying agent), obtain 2- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- diazas Cycloheptane -1- base) pyridine -2- base) sulfenyl) methyl) phenyl) acetic acid (126mg) is white solid.LCMS m/z=450.3 [M+H]+。
Step 2:2- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyrrole Pyridine -2- base) sulfenyl) methyl) phenyl)-N- (2- hydroxyethyl) acetamide
In room temperature, to 2- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) Pyridine -2- base) sulfenyl) methyl) phenyl) acetic acid (50mg, 0.111mmol) is molten in n,N-Dimethylformamide (0.7mL) HATU (44mg, 0.116mmol) is added in liquid.Then the reaction mixture is stirred at room temperature 20 minutes, ethyl alcohol is added at this time Amine (7.2 μ L, 0.119mmol).Then the reaction mixture is stirred at room temperature, while monitors process with LCMS.After 4 hours, The mixture is filtered, which is purified into (Gilson, 30mm x 50mm Gemini column, NH with reversed-phase HPLC4OH is modified Agent), obtain 2- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) phenyl)-N- (2- hydroxyethyl) acetamide (41mg) is white solid.LCMS m/z=493.3 [M+H ]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.06 (t, J=5.45Hz, 1H), 7.28-7.34 (m, J=8.11Hz, 2H), 7.15-7.25 (m, J=8.11Hz, 2H), 4.69 (t, J=5.45Hz, 1H), 4.47 (s, 2H), 3.82-3.95 (m, 4H), 3.36-3.42 6 (m, 4H), 3.10 (q, J=6.08Hz, 2H), 2.78 (q, J=7.60Hz, 2H), 2.62-2.68 (m, 2H), (2.48 d, J=5.58Hz, 2H), 2.24 (s, 3H), 1.88-1.97 (m, 2H), 1.22 (t, J=7.60Hz, 3H).
Embodiment 344:
2- (((1H- indoles -5- base) methyl) sulfenyl) -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyrrole Pyridine -3,5- dimethoxy nitrile
Step 1:5- formoxyl -1H- indoles -1- t-butyl formate
To 1H- indoles -5- formaldehyde (2.5g, 17.22mmol), triethylamine (4.36g, 43.1mmol) and N, N- dimethyl N, N- lutidines -4- amine is added in pyridine -4- amine (0.021g, 0.172mmol) in the solution in methylene chloride (30mL) (0.021g, 0.172mmol).The reaction mixture is stirred at room temperature overnight.Acquired solution is diluted with water (30mL), uses second Acetoacetic ester (3x 20mL) extraction.Organic layer is merged, with aqueous sodium carbonate and salt water washing, dries, filters and vacuum is dense Contracting, obtains 5- formoxyl -1H- indoles -1- t-butyl formate (2.96g, 12.06mmol, 70% yield), is yellow oil. LCMS m/z=246.1 [M+H]+。
Step 2:5- (hydroxymethyl) -1H- indoles -1- t-butyl formate
At 0 DEG C, to 5- formoxyl -1H- indoles -1- t-butyl formate (3.0g, 12.23mmol) in methanol (30mL) Solution in be added Sodium Borohydride (0.463g, 12.23mmol).The reaction mixture is stirred 3 hours at 0 DEG C, is then existed It is stirred overnight at room temperature.Acquired solution is diluted with water (40mL), is then extracted with ethyl acetate (3x 30mL).It will be organic laminated It is dry to be simultaneously concentrated in vacuo and with aqueous sodium carbonate and salt water washing, obtain 5- (hydroxymethyl) -1H- indoles -1- formic acid uncle Butyl ester (2.5g, 10.11mmol, 83% yield), is yellow oil.LCMS m/z=270.3 [M+Na]+。
The chloro- 4- ethyl -6- of step 3:2- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -3,5- dimethoxy nitrile
To chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (describe synthesis in 3 step 2 of embodiment, 500mg, 2.21mmol) and 4- (- 1 base of pyrrolidines) piperidines is added in triethylamine (336mg, 3.32mmol) in the solution in acetonitrile (20mL) (341mg, 2.21mmol).The reaction mixture is stirred at room temperature overnight.Acquired solution is diluted with water (50mL), is then used Ethyl acetate (3x 20mL) extraction.Organic layer is merged, with aqueous sodium carbonate and salt water washing, dries, filters and vacuum is dense Contracting.The residue is applied on silicagel column and (is eluted with ethyl acetate/hexane 1/20), the chloro- 4- ethyl -6- (4- (pyrrole of 2- is obtained Cough up alkane -1- base) piperidin-1-yl) pyridine -3,5- dimethoxy nitrile (620mg, 1.80mmol, 82% yield) is yellow solid. LCMS m/z=344.2 [M+H]+。
Step 4:5- (((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- base) Sulfenyl) methyl) -1H- indoles -1- t-butyl formate
At 0 DEG C, to 5- (hydroxymethyl) -1H- indoles -1- t-butyl formate (2.8g, 11.32mmol), triethylamine Methane sulfonyl chloride (1.297g, 11.32mmol) is added dropwise in the solution in methylene chloride (30mL) in (1.719g, 16.98mmol). The reaction mixture is stirred at room temperature 3 hours.Acquired solution is diluted with water (20mL), is extracted with ethyl acetate (3x 15mL) It takes.Organic layer is merged, with aqueous sodium carbonate and salt water washing, drying is simultaneously concentrated in vacuo, and obtains yellow oil (3.1g).To 2- Chloro- 4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -3,5- dimethoxy nitrile (620mg, 1.80mmol) is in N, N- bis- Thioacetic acid potassium (247mg, 2.16mmol) is added in solution in methylformamide (15mL).By the reaction mixture in room temperature After stirring 30 minutes, above-mentioned yellow oil (645mg) and triethylamine (456mg, 4.51mmol) are added in the reaction and by this instead Mixture is answered to be stirred at room temperature overnight.Water (20mL) is added and extracts acquired solution with ethyl acetate (3x 20mL).It will be organic It is laminated simultaneously, with aqueous sodium carbonate and salt water washing, dry, filter and be concentrated in vacuo.The residue is purified on a silica gel column (being eluted with ethyl/MeOH/DCM 1/20), obtains 5- (((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidines - 1- yl) pyridine -2- base) sulfenyl) methyl) -1H- indoles -1- t-butyl formate (340mg, 0.60mmol) is yellow solid. LCMS m/z=571.4 [M+H]+。
Step 5:2- (((1H- indoles -5- base) methyl) sulfenyl) -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidines -1- Base) pyridine -3,5- dimethoxy nitrile
By 5- (((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- base) sulfenyl) Methyl) the solution reflux of -1H- indoles -1- t-butyl formate (120mg, 0.21mmol) in DCM (3mL).Then by trifluoro second Sour (0.016mL, 0.21mmol) is added in the reaction and the mixture is flowed back 10 minutes.The reaction mixture is cooled to room Temperature and by the pH Na of the solution2CO3It is adjusted to 10~11.Acquired solution is extracted with DCM (3x 10mL).It will be organic laminated It is dry to be simultaneously concentrated in vacuo and with aqueous sodium carbonate and salt water washing.Residue preparative-HPLC is purified, 2- is obtained (((1H- indoles -5- base) methyl) sulfenyl) -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -3,5- dimethoxy nitrile (30mg, 0.06mmol, 30% yield), is yellow solid.LCMS m/z=471.1 [M+H]+。1H NMR (400MHz, CDCl3) δ ppm 8.36 (s, 1H), 7.65 (s, 1H), 7.38 (d, J=8.3Hz, 1H), 7.27-7.15 (m, 2H), 6.53 (s, 1H), 4.62 (d, J=13.5Hz, 2H), 4.55 (s, 2H), 3.26 (t, J=11.7Hz, 2H), 2.91 (q, J=7.6Hz, 2H), 2.65 (s, 4H), 2.42 (s, 1H), 2.04 (d, J=11.0Hz, 2H), 1.85 (s, 4H), 1.70-1.59 (m, 2H), 1.33 (t, J=7.6Hz, 3H).
Embodiment 345:
4- (((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) methyl) benzene sulfonyl Amine
Step 1:(1- (3,5- dicyano -4- ethyl -6- ((4- sulfamoylbenzyl) sulfenyl) pyridine -2- base) piperidines - 4- yl) t-butyl carbamate
In room temperature, to (1- (chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-) piperidin-4-yl) the tertiary fourth of carbamic acid Sulphur is added in the solution in n,N-Dimethylformamide (10mL) in ester (describing synthesis, 1.5g in 81 step 1 of embodiment) For potassium acetate (0.659g, 5.77mmol), it is stirred at room temperature 2 hours.To potassium carbonate being added in the reaction mixture (1.063g, 7.69mmol) and 4- (bromomethyl) benzsulfamide (0.962g, 3.85mmol) simultaneously stirs gained mixture in room temperature It mixes 16 hours.Water (20mL) is added and extracts the mixture with ethyl acetate (2x 20mL).By organic layer anhydrous Na2SO4 It is dried, filtered and concentrated.The crude compound is passed through into silica gel chromatography (100-200, with 30-40% ethyl acetate/stone Oily ether elution), obtain (1- (3,5- dicyano -4- ethyl -6- ((4- sulfamoylbenzyl) sulfenyl) pyridine -2- base) piperidines -4- Base) t-butyl carbamate (750mg) is pale solid.LCMS m/z=557.0 [M+H]+。
Step 2:4- (((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) methyl) Benzsulfamide
At 0 DEG C, to (1- (3,5- dicyano -4- ethyl -6- ((4- sulfamoylbenzyl) sulfenyl) pyridine -2- base) piperazine Pyridine -4- base) HCl (1,4- of 4M is added in t-butyl carbamate (500mg) in the agitating solution in 1,4- dioxanes (5mL) Dioxane, 5mL, 20mmol), it is stirred at room temperature 4 hours.The reaction mixture is concentrated under reduced pressure, ether is then used (2x 10mL) washing, obtains the crude product.Crude material preparative-HPLC is purified, 4- (((6- (4- amino piperazine is obtained Pyridine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) methyl) benzsulfamide (150mg, 38% yield), for ash White solid.LCMS m/z=457.0 [M+H]+。1H NMR (400MHz, DMSO-d6, D2O exchange) δ ppm 7.77 (d, J=8.4Hz, 2H), 7.59 (d, J=8.4Hz, 2H), 4.56 (s, 2H), 4.38-4.31 (m, 2H), 3.30-3.24 (m, 2H), 2.93-2.83 (m, 1H), 2.76 (q, J=7.60Hz, 2H), 1.80 (br dd, J=13.26,3.62Hz, 2H), 1.30-1.17 (m, 5H).4 protons do not measure.
Embodiment 346
2- ((benzo [d] [1,3] dioxole -5- ylmethyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- bis- Azepan -1- base) pyridine -3,5- dimethoxy nitrile
Benzo [d] [1,3] dioxole -5- base methanol (60mg, 0.394mmol) is molten in ether (5mL) Liquid is handled with thionyl chloride (0.029mL, 0.394mmol), then uses n,N-diisopropylethylamine (0.069mL, 0.394mmol) It handles and stirs 2 hours, be then concentrated.Twice with chloroform azeotropic by the residue.It is molten in chloroform (5mL) to the residue N,N-diisopropylethylamine (0.069mL, 0.394mmol) is added in liquid, 4- ethyl -2- sulfydryl -6- (4- methyl-is then added Isosorbide-5-Nitrae-Diazesuberane -1- base) pyridine -3,5- dimethoxy nitrile (describe synthesis in embodiment 69, step 1,149mg, 0.394mmol) and by the reaction it is stirred overnight.Gradient silica gel chromatograph uses 0% methanol/0%NH4OH is in methylene chloride Solution is to 5% methanol/1%NH4Then the solution of OH in methylene chloride crystallizes from ether as eluant, eluent, obtains 2- ((benzo [d] [1,3] dioxole -5- ylmethyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- Diazesuberane - 1- yl) pyridine -3,5- dimethoxy nitrile (34mg, 20% yield).LCMS m/z 436.2[M+H]+。1H NMR (400MHz, MeOH- d4) δ ppm 1.32 (t, 3H), 2.01-2.14 (m, 2H), 2.38 (s, 3H), 2.59-2.69 (m, 2H), 2.73-2.82 (m, 2H), 2.87-2.97 (m, 2H), 3.94-4.06 (m, 4H), 4.44 (s, 2H), 5.95 (s, 2H), 6.74-6.82 (m, 1H), 6.90 (m, 2H).
Embodiment 347
2- (((3,3- dimethoxy -2- oxoindoline -5- base) methyl) sulfenyl) -4- ethyl -6- (4- methyl-1, 4- Diazesuberane -1- base) pyridine -3,5- dimethoxy nitrile
Step 1:5- methyl -2,3- dioxo indoline -1- t-butyl formate
At 20 DEG C, to 5- methyl indoline -2,3- diketone (5.15g, 32.0mmol) and Boc- acid anhydrides (7.67g, DMAP (0.10g, 0.819mmol) 35.2mmol) is added in the mixture in THF (50mL).Mixture stirring 1 is small When, yellow solid is then flashed to, pulp in ether by it.Solid is collected to and used heptane wash, obtains 5- methyl -2,3- Dioxo indoline -1- t-butyl formate (4.5g, 54% yield).LCMS m/z=284.0 [M+Na]+。
Step 2:5- (bromomethyl) -2,3- dioxo indoline -1- t-butyl formate
By 5- methyl -2,3- dioxo indoline -1- t-butyl formate (4.25g, 16.27mmol), NBS (3.2g, 17.98mmol) exist with the mixture of benzoyl peroxide (30mg, 0.124mmol) in carbon tetrachloride (20ml, 207mmol) 80 DEG C are stirred 3 hours.The mixture is directly thickened on silica gel and with gradient flash chromatography, uses 100% heptane to 100% Methylene chloride as eluent, obtain 5- (bromomethyl) -2,3- dioxo indoline -1- t-butyl formate (3.1g, 9.11mmol 56% yield), it is yellow solid.LCMS m/z 362.0[M+Na]+。
Step 3:2- (((3,3- dimethoxy -2- oxoindoline -5- base) methyl) sulfenyl) -4- ethyl -6- (4- Methyl-1,4- Diazesuberane -1- base) pyridine -3,5- dimethoxy nitrile
By 4- ethyl -2- sulfydryl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -3,5- dimethoxy nitrile (in reality Apply example 69, synthesis, 177mg, 0.470mmol described in step 1) and triethylamine (0.197mL, 1.411mmol) in chloroform Solution in (25mL) stirs in ice salt bath, by the way that the tertiary fourth of 5- (bromomethyl) -2,3- dioxo indoline -1- formic acid is added dropwise Solution of the ester (160mg, 0.470mmol) in chloroform (25mL) is handled and is stirred overnight, so that the mixture reaches environment temperature Degree.The solution is evaporated to low volume and with gradient silica gel chromatography, using methylene chloride to 25% ethyl alcohol, 1% methanol, The ethyl acetate solution of 1% ammonium hydroxide.The product of elution is concentrated and 4M is added in the solution in chloroform (5mL) to the residue The dioxane (3mL, 99mmol) of HCl.The solution is stirred overnight to and is used gradient reverse-phase chromatography, uses 30-80% acetonitrile- The purifying aqueous solutions of 1% ammonium hydroxide obtain 2- (((3,3- dimethoxy -2- oxoindoline -5- base) methyl) sulfenyl) -4- second Base -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -3,5- dimethoxy nitrile (55mg, 23% yield).LCMS m/z= 507.2[M+H]+。1H NMR (400MHz, methanol-d4) δ ppm 1.32 (t, J=7.60Hz, 3H), 2.00-2.12 (m, 2H), 2.35 (s, 3H), 2.57-2.66 (m, 2H), 2.68-2.77 (m, 2H), 2.88-2.98 (m, 2H), 3.50 (s, 6H), 3.98 (d, J=5.83Hz, 4H), 4.52 (s, 2H), 6.83-6.91 (m, 1H), 7.36-7.43 (m, 1H), 7.44-7.52 (m, 1H).
Embodiment 348
2- (((2,3- dioxo indoline -5- base) methyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- diaza Cycloheptane -1- base) pyridine -3,5- dimethoxy nitrile
(embodiment 347, what step 3) also separated is 2- (((2,3- dioxo indoline -5- base) first for above-mentioned reaction Base) sulfenyl) -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -3,5- dimethoxy nitrile (12mg, 0.026mmol, 6% yield).LCMS m/z=461.1 [M+H]+.1H NMR (400MHz, methanol-d4) ppm 1.32 (t, 3H), 2.04-2.13 (m, 2H), 2.41 (s, 3H), 2.65-2.73 (m, 2H), 2.75-2.86 (m, 2H), 2.89-2.97 (m, 2H), 3.95-4.03 (m, 4H), 4.51 (s, 2H), 6.83-6.97 (m, 1H), 7.35-7.69 (m, 2H).
Embodiment 349
N- (4- (((6- (((4H-1,2,4- triazole -3- base) methyl) (methyl) amino) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) sulfenyl) methyl) benzyl) acetamide
By N- (4- (bromomethyl) benzyl) acetamide (130mg, 0.535mmol) and thioacetic acid potassium (72.2mg, 0.633mmol) the first reaction mixture in ethyl alcohol (3mL) stirs 20 minutes at 60 DEG C, and NaBH is then added4(36.8mg, 0.973mmol) and at 60 DEG C 2 stir 20 minutes.To chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (in embodiment 3, step Synthesis, 110mg, 0.487mmol are described in 2) be slowly added in the solution in DMF (1.0mL) N- methyl-1-(4H-1,2, 4- triazole -3- base) methylamine, hydrochloride (84mg, 0.535mmol) and TEA (0.136mL, 0.973mmol) are in DMF (2.0mL) Pulp solution.Second reaction mixture is stirred at room temperature 20 minutes.First and second reaction mixture is merged And it is stirred at room temperature overnight.It adds more TEA (0.136mL, 0.973mmol) and is stirred for 2 hours.By the reaction mixture It filters and purifies (10-40% acetonitrile/water, 0.1%NH with RP-HPLC4The aqueous solution of OH), obtain N- (4- (((6- (((4H-1, 2,4- triazole -3- base) methyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) methyl) benzyl) acetyl Amine (55mg, 0.119mmol, 25% yield), is pale solid.LCMS m/z=461.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 1.22 (t, J=7.6Hz, 3H), 1.86 (s, 3H), 2.78 (q, J=7.6Hz, 2H), 3.51 (s, 3H), 4.21 (d, J=5.8Hz, 2H), 4.36 (s, 2H), 5.06 (s, 2H), 7.17 (m, J=8.1Hz, 2H), 7.25 (m, J =8.1Hz, 2H), 8.33 (d, J=5.8Hz, 2H).1 proton does not measure.
Embodiment 350:
4- ethyl -2- ((4- (pyridine -2- base) benzyl) sulfenyl) -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine - 3,5- dimethoxy nitrile
To 4,4,4', 4', 5,5,5', 5'- prestox -2,2'- bis- (1,3,2- dioxaborolan alkane) (418mg, 1.65mmol), potassium acetate (202mg, 2.06mmol), 2- ((4- bromobenzyl) sulfenyl) -4- ethyl -6- (4- (pyrrolidin-1-yl) Piperidin-1-yl) pyridine -3,5- dimethoxy nitrile (describing synthesis, 700mg, 1.37mmol in 337 step 4 of embodiment) is in Isosorbide-5-Nitrae - (diphenylphosphine) ferrocene of 1,1'- bis- palladium chloride (II) chloride dichloromethane complex is added in solution in dioxanes (8mL) (100mg, 0.14mmol).By the mixture 90 DEG C stirred under Ar atmosphere 15 hours.By potassium carbonate (284mg, 2.06mmol), 1,1'- bis- (diphenylphosphine) ferrocene palladium chloride (II) chloride dichloromethane complex (100mg, 0.14mmol), water (2mL) and 2- Chloropyridine (234mg, 2.06mmol) adds to the solution.By the reaction 100 DEG C stirred under Ar atmosphere 18 hours, then vacuum is dense It contracts and is purified with preparative-HPLC, obtain 4- ethyl -2- ((4- (pyridine -2- base) benzyl) sulfenyl) -6- (4- (pyrrolidines -1- Base) piperidin-1-yl) pyridine -3,5- dimethoxy nitrile (41mg, 6% yield) is light yellow solid.LCMS m/z=508.9 [M+ H]+。1H NMR (400MHz, CDCl3) δ ppm 8.68 (d, J=4.6Hz, 1H), 7.96 (d, J=8.2Hz, 2H), 7.79-7.70 (m, 2H), 7.48 (d, J=8.2Hz, 2H), 7.26-7.22 (m, 1H), 4.55 (d, J=13.5Hz, 2H), 4.46 (s, 2H), 3.21 (t, J=11.8Hz, 2H), 2.90 (q, J=7.6Hz, 2H), 2.72-2.52 (m, 4H), 2.45-2.33 (m, 1H), 2.04-1.96 (m, 2H), 1.85-1.76 (m, 4H), 1.68-1.57 (m, 2H), 1.32 (t, J=7.6Hz, 3H).
Embodiment 351:
2- ((3,5- dicyano -4,6- parvoline -2- base) sulfenyl) -2- phenyl-acetamides
Step 1:4,6- diethyl -2- oxo -1,2- dihydropyridine -3- formonitrile HCN
In room temperature, KOH (2.408g, 42.9mmol) is added into heptane -3,5- diketone (5g, 39.0mmol) and 2- cyano Acetamide (3.44g, 41.0mmol) stirs 14 in the mixture of the stirring in methanol (200mL) and by the mixture at 80 DEG C Hour.Then it is concentrated in vacuo to remove the solvent, which is dissolved in water and dilute HCl solution is added so that the solution Obtained solid is filtered in pH~3, obtains 4,6- diethyl -2- oxo -1,2- dihydropyridine -3- formonitrile HCN (5.8g).LCMS m/z =177.2 [M+H]+。
The bromo- 4,6- diethyl -2- oxo -1,2- dihydropyridine -3- formonitrile HCN of step 2:5-
At 0 DEG C, NBS (7.68g, 43.1mmol) is added into 4,6- diethyl -2- oxo -1,2- dihydropyridine -3- formonitrile HCN (3.8g, 21.56mmol) stirring in 2,2,2- trifluoroacetic acids (15mL, 21.56mmol) and sulfuric acid (15mL, 21.56mmol) It mixes in solution, which is stirred 14 hours.Then the mixture is poured into trash ice water and filters obtained solid, obtained Bromo- 4,6- diethyl -2- oxo -1, the 2- dihydropyridine -3- formonitrile HCN (4.2g, 16.46mmol, 76%) of 5-.LCMS m/z= 255.0,257.0 [M+H]+。
Step 3:4,6- diethyl -2- oxo -1,2- dihydropyridine -3,5- dimethoxy nitrile
By bromo- 4,6- diethyl -2- oxo -1, the 2- dihydropyridine -3- formonitrile HCN (2.2g, 8.62mmol) of 5- and cyano copper It is small that the mixture of (0.927g, 10.35mmol) in n-methyl-2-pyrrolidone (30mL) stirs 24 under 170 DEG C of nitrogen atmosphere When.Then it will be removed under the solvent high vacuum.The residue column chromatography is purified (petroleum ether: ethyl acetate=2:1), is obtained 4,6- diethyl -2- oxo -1,2- dihydropyridine -3,5- dimethoxy nitriles (490mg, 2.44mmol, 28% yield).LCMS m/z= 202.2[M+H]+。
The chloro- 4,6- parvoline -3,5- dimethoxy nitrile of step 4:2-
By 4,6- diethyl -2- oxo -1,2- dihydropyridine -3,5- dimethoxy nitrile (490mg, 2.44mmol) and trichlorine oxygen The mixture of phosphorus (15mL, 2.44mmol) stirs 20 hours in 155 DEG C of sealed tubes.The mixture is concentrated in vacuo to remove this Solvent.The residue column chromatography is purified (petrol ether/ethyl acetate=4/1), chloro- parvoline -3 4,6- 2- are obtained, 5- dimethoxy nitrile (354mg, 1.61mmol, 66% yield).1H NMR (400MHz, CDCl3) δ 3.11 (m, 4H), 1.41 (m, 6H).
Step 5:2- ((3,5- dicyano -4,6- parvoline -2- base) sulfenyl) -2- phenyl-acetamides
By chloro- 4,6- parvoline -3, the 5- dimethoxy nitrile (330mg, 1.50mmol) of 2-, 2- sulfydryl -2- phenyl-acetamides (describing synthesis, 377mg, 2.25mmol in 276 step 1 of embodiment) and triethylamine (0.628mL, 4.51mmol) are in DMF Mixture in (20mL) stirs 14 hours at 20 DEG C.Then it adds water to and is extracted with ethyl acetate, organic layer is concentrated, it will The residue is purified with column chromatography, obtains 2- ((3,5- dicyano -4,6- parvoline -2- base) sulfenyl) -2- phenylacetyl Amine (93mg, 18%).LCMS m/z=373.2 [M+Na]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.97 (s, 1H), 7.57 (m, 2H), 7.42-7.26 (m, 4H), 5.76 (s, 1H), 2.99 (q, J=7.5Hz, 2H), 2.85 (q, J=7.6Hz, 2H), 1.30 (t, J=7.5Hz, 3H), 1.22 (t, J=7.6Hz, 3H).
Embodiment 352
2- ((6- ((2- (4H-1,2,4- triazole-4-yl) ethyl) (methyl) amino) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) sulfenyl) -2- phenyl-acetamides
Step 1:2- ((2- (4H-1,2,4- triazole-4-yl) ethyl) (methyl) amino) chloro- ethylpyridine -3 4- -6-, 5- dimethoxy nitrile
To N- methyl -2- (4H-1,2,4- triazole-4-yls) ethamine (335mg, 2.65mmol) at methylene chloride (20mL) Triethylamine (1.151mL, 7.96mmol) is added in middle agitating solution, chloro- 4- ethylpyridine -3, the 5- diformazan of 2,6- bis- is then added Nitrile (describes synthesis, 600mg, 2.65mmol in 3 step 2 of embodiment).The reaction mixture is stirred at room temperature 1 hour. Water (40mL) is added and extracts the mixture with DCM (2x 23mL).By combined organic layer Na2SO4It dries and depressurizes dense Contracting, obtains the roughage.By crude material silica gel chromatography (60-120 mesh；The EtOAc solution of 10%MeOH is used as and washes De- agent), obtain 2- ((2- (4H-1,2,4- triazole-4-yls) ethyl) (methyl) amino) chloro- 4- ethylpyridine -3,5- diformazan of -6- Nitrile (500mg).LCMS m/z=316.0 [M+H]+。
Step 2:2- ((6- ((2- (4H-1,2,4- triazole-4-yl) ethyl) (methyl) amino) -3,5- dicyano -4- second Yl pyridines -2- base) sulfenyl) -2- phenyl-acetamides
To 2- ((2- (4H-1,2,4- triazole-4-yl) ethyl) (methyl) amino) the chloro- 4- ethylpyridine -3,5- two of -6- Thioacetic acid potassium is added in the agitating solution in n,N-Dimethylformamide (20mL) in formonitrile HCN (500mg, 1.583mmol) (271mg, 2.375mmol).The reaction mixture is stirred at room temperature 30 minutes.K is added2CO3(328mg, 2.375mmol), so Be added afterwards methanesulfonic acid 2- amino -2- oxo -1- phenylethylester (describe synthesis in 3 step 5 of embodiment, 363mg, 1.583mmol).The reaction mixture is stirred at room temperature 16 hours.Water (100mL) is added and by the mixture ethyl acetate (2x 50mL) extraction.By combined organic layer Na2SO4It dries and is concentrated under reduced pressure, obtain crude product.By the crude material With silica gel chromatography (60-120 mesh；3%MeOH/CH2Cl2As eluant, eluent), residue is obtained, pentane is used (20mL) washing, obtains 2- ((6- ((2- (4H-1,2,4- triazole-4-yls) ethyl) (methyl) amino) -3,5- dicyano -4- second Yl pyridines -2- base) sulfenyl) -2- phenyl-acetamides (260mg).LCMS m/z=447.2 [M+H]+。1H NMR (400MHz, chlorine Imitative-d) δ ppm 8.32 (s, 2H), 7.48-7.36 (m, 5H), 6.63 (br s, 1H), 5.76 (br s, 1H), 5.21 (s, 1H), 4.38-4.30 (m, 3H), 4.08-3.98 (m, 1H), 3.43 (s, 3H), 2.98-2.90 (q, J=7.6Hz, 2H), 1.34 (t, J =7.2Hz, 3H).
Embodiment 354
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) phenyl)-N- methylacetamide
Step 1:4- ethyl -2- (4- methyl-1,4- Diazesuberane -1- base) -6- ((4- (methylamino) benzyl) Sulfenyl) pyridine -3,5- dimethoxy nitrile
To 4- ethyl -2- sulfydryl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -3,5- dimethoxy nitrile (in reality Apply example 69, synthesis, 400mg, 1.062mmol described in step 1) and TEA (0.296mL, 2.123mmol) in DMF (4mL) Solution in be added (4- (bromomethyl) phenyl) (methyl) t-butyl carbamate (335mg, 1.062mmol) in DMF (2mL) Solution.The reaction mixture is stirred at room temperature 2 hours.Reaction mixture RP-HPLC is purified (50-80% acetonitrile/ Water, the aqueous solution of 0.1%NH4OH), obtain pale yellow waxy solid.To the solution of above-mentioned solid in methylene chloride (4.00mL) is added in TFA (1mL, 12.98mmol), stirs 1 hour.The reaction mixture is concentrated, which is distributed Between DCM and water, NH is then used4OH alkalization.It separates each layer and washes twice with DCM water layer above.By combined slurries Organic matter is washed with water, and is then mixed to get clear solution with some methanol, uses Na2SO4Dry, concentration obtains 4- ethyl -2- (4- methyl-1,4- Diazesuberane -1- base) -6- ((4- (methylamino) benzyl) sulfenyl) pyridine -3,5- dimethoxy nitrile (190mg, 0.452mmol, 43% yield), is pale solid.LCMS m/z=421.4 [M+H]+。
Step 2:N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyrrole Pyridine -2- base) sulfenyl) methyl) phenyl)-N- methylacetamide
At 0 DEG C, to 4- ethyl -2- (4- methyl-1,4- Diazesuberane -1- base) -6- ((4- (methylamino) benzyl Base) sulfenyl) pyridine -3,5- dimethoxy nitrile (50mg, 0.119mmol) and TEA (0.033mL, 0.238mmol) be in THF (2mL) The solution of chloroacetic chloride (0.013mL, 0.178mmol) in THF (0.5mL) is added dropwise in solution.The reaction mixture is stirred 20 Minute.The reaction mixture is concentrated and purifies (30-40% acetonitrile/water, 0.1%NH with RP-HPLC4The aqueous solution of OH), it obtains To N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) first Base) phenyl)-N- methylacetamide (38mg, 0.082mmol, 69% yield) is canescence vitreous solid.LCMS m/z =463.2 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 1.23 (t, J=7.6Hz, 3H), 1.76 (br.s., 3H), 1.86-1.95 (m, 2H), 2.23 (s, 3H), 2.44-2.49 (m, 2H), 2.60-2.69 (m, 2H), 2.79 (q, J=7.6Hz, 2H), 3.12 (br.s., 3H), 3.79-3.95 (m, 4H), 4.53 (s, 2H), 7.30 (m, J=7.9Hz, 2H), 7.46 (m, J= 7.9Hz, 2H).
Embodiment 355
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) phenyl)-N- methyl methyl sulfonamide
At 0 DEG C, to 4- ethyl -2- (4- methyl-1,4- Diazesuberane -1- base) -6- ((4- (methylamino) benzyl Base) sulfenyl) pyridine -3,5- dimethoxy nitrile (synthesis, 50mg, 0.119mmol are described in embodiment 354, step 1) and TEA Methane sulfonyl chloride (0.028mL, 0.357mmol) is added dropwise in THF in (0.033mL, 0.238mmol) in the solution in THF (2mL) Solution in (0.5mL).The reaction mixture is stirred overnight.The reaction mixture is concentrated and purifies (30- with RP-HPLC 50% acetonitrile/water, 0.1%NH4The aqueous solution of OH), obtain N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) methyl) phenyl)-N- methyl methyl sulfonamide (37mg, 0.074mmol, 62% yield), it is pale solid.LCMS m/z=499.2 [M+H]+。1H NMR (400MHz, DMSO-d6)δppm 1.22 (t, J=7.6Hz, 3H), 1.83-1.98 (m, 2H), 2.24 (s, 3H), 2.48-2.45 (m, 2H), 2.61-2.70 (m, 2H), 2.78 (q, J=7.6Hz, 2H), 2.93 (s, 3H), 3.22 (s, 3H), 3.80-3.94 (m, 4H), 4.51 (s, 2H), 7.33- 7.40 (m, 2H), 7.40-7.47 (m, 2H).
Embodiment 356:
2- ((6- (((1H- pyrazole-3-yl) methyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides
Step 1:(1H- pyrazole-3-yl) methanol
To in the aluminum hydride of 0 DEG C of stirred under nitrogen (III) lithium (2.71g, 71.4mmol) in tetrahydrofuran (20mL) 1H- pyrazoles -3- formic acid (4g, 35.7mmol) is added in solution.The reaction mixture is stirred at room temperature 1 hour, is then refluxed for Overnight.The mixture is cooled to 0 DEG C.Then by the reaction by be added water (2.7mL), then be added NaOH solution (10%, 5.4mL), water (8.1mL) is then added to be quenched.The mixture is stirred 30 minutes at 0 DEG C, is then passed throughIt padded Filter.The solvent under reduced pressure is removed and (elutes the residue silica gel column purification) with ethyl acetate/hexane 1/2, obtains (1H- Pyrazole-3-yl) methanol (1.9g, 19.37mmol, 54% yield) is yellow oil.LCMS m/z=81.1 [M+H-H2O]+。
Step 2:3- (chloromethyl) -1H- pyrazoles
To (1H- pyrazole-3-yl) methanol (1.9g, 19.37mmol) in 0 DEG C of stirred under nitrogen in methylene chloride The solution of thionyl chloride (5.76g, 48.4mmol) in DCM (5.0mL) is added in solution in (20mL).The reaction is mixed Object stirs 2 hours at 0 DEG C.The reaction mixture is warmed to room temperature.Acquired solution water and ice are diluted.Then bicarbonate is used Sodium water solution is adjusted to pH 6~7.Acquired solution is extracted with ethyl acetate (3x 30mL).Organic layer is merged, sodium carbonate is used Aqueous solution and salt water washing, drying are simultaneously concentrated in vacuo, and obtaining 3- (chloromethyl) -1H- pyrazoles, (0.9g, 7.72mmol, 40% are produced Rate), it is yellow oil.LCMS m/z=117.0 [M+H]+。
Step 3:N- methyl-1-(1H- pyrazole-3-yl) methylamine
Solution of the methylamine (311mg, 10mmol) in tetrahydrofuran (5mL) is added dropwise to 3- (chloromethyl) -1H- pyrazoles (300mg, 2.57mmol) is in the solution in tetrahydrofuran (5mL).The mixture is stirred at room temperature 10 minutes.By the solvent It is removed by vacuum distillation, obtains N- methyl-1-(1H- pyrazole-3-yl) methylamine (300mg, 1.62mmol, 63% yield), For yellow oil.LCMS m/z=112.1 [M+H]+。
Step 4:2- (((1H- pyrazole-3-yl) methyl) (methyl) amino) chloro- 4- ethylpyridine -3,5- dimethoxy nitrile of -6-
It (is described in 3 step 2 of embodiment to the chloro- 4- ethylpyridine -3,5- dimethoxy nitrile of 2,6- bis- being stirred at room temperature Synthesis, 366mg, 1.62mmol) and triethylamine (246mg, 2.43mmol) N- methyl-is added in the solution in acetonitrile (15mL) Solution of 1- (1H- pyrazole-3-yl) methylamine (300mg, 1.62mmol) in acetonitrile (5mL) and by the reaction mixture in room temperature Stirring 2 hours.Acquired solution is diluted with water (50mL), is then extracted with ethyl acetate (3x 20mL).Organic layer is merged, With aqueous sodium carbonate and salt water washing, dries, filters and be concentrated in vacuo.Residue silica gel column purification (is used into acetic acid second Ester/hexane 1/2 elutes), obtain 2- (((1H- pyrazoles -4- base) methyl) (methyl) amino) chloro- 4- ethylpyridine -3,5- bis- of -6- Formonitrile HCN (200mg, 0.67mmol, 41% yield), is yellow oil.LCMS m/z=301.0 [M+H]+。
Step 5:2- ((6- (((1H- pyrazole-3-yl) methyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine - 2- yl) sulfenyl) -2- phenyl-acetamides
Two individually reactions are carried out, them is combined and post-processes.By 2- (((1H- pyrazole-3-yl) methyl) (first Base) amino) chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile (170mg, 0.57mmol) of -6- and thioacetic acid potassium (194mg, 1.70mmol) solution in N,N-dimethylformamide (10mL) is stirred at room temperature 20 minutes.Then the bromo- 2- phenyl of 2- is added Acetamide (423mg, 1.98mmol) and triethylamine (0.315mL, 2.26mmol).The mixture is stirred at room temperature overnight.Point Open ground, by 2- (((1H- pyrazole-3-yl) methyl) (methyl) amino) chloro- 4- ethylpyridine -3,5- dimethoxy nitrile of -6- (30mg, 0.100mmol) exist with the solution of thioacetic acid potassium (22.78mg, 0.200mmol) in n,N-Dimethylformamide (5.0mL) It is stirred at room temperature 20 minutes.Then be added the bromo- 2- phenyl-acetamides (53.4mg, 0.249mmol) of 2- and TEA (0.056mL, 0.399mmol).The mixture is stirred at room temperature overnight.Two reaction mixtures are merged.Water (30mL) is added and by gained Solution is extracted with ethyl acetate (3x 20mL).Organic layer is merged, with aqueous sodium carbonate and salt water washing, dry and vacuum Concentration.The residue is purified into (being eluted with ethyl acetate) with preparative-TLC, obtains 2- ((6- (((1H- pyrazole-3-yl) first Base) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides (84mg, 0.19mmol, 34% yield), it is white solid.LCMS m/z=432.1 [M+H]+。1H NMR (400MHz, DMSO-d6)δppm 12.82 (s, 1H), 7.93 (s, 1H), 7.73 (s, 1H), 7.46 (d, J=6.4Hz, 2H), 7.34 (d, J=7.2Hz, 4H), 6.22 (d, J =2.0Hz, 1H), 5.60 (s, 1H), 5.20 (d, J=15.6Hz, 1H), 4.87 (d, J=16.0Hz, 1H), 3.32 (s, 3H), 2.77 (q, J=7.3Hz, 2H), 1.21 (t, J=7.6Hz, 3H).
Embodiment 357
4- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base sulfenyl) Methyl) phenylboric acid
To 4- ethyl -2- sulfydryl -6- (4- methyl-1, the 4- Diazesuberane -1- base) pyrrole stirred in 20 DEG C of air Pyridine -3,5- dimethoxy nitrile (describing synthesis, 400mg, 1.33mmol in 69 step 1 of embodiment) is in n,N-Dimethylformamide Be added in solution in (15mL) (4- (bromomethyl) phenyl) boric acid (285mg, 1.33mmol) and triethylamine (0.37mL, 2.65mmol).The reaction mixture is stirred 5 hours at 25 DEG C.The reaction mixture is quenched with water and will be formed by it is heavy Shallow lake is collected by filtration, be dried in vacuo and by the residue flash column chromatography, obtain 4- ((3,5- dicyano -4- second Base -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base sulfenyl) methyl) phenylboric acid (260mg, 45%), For orange solids.LCMS m/z=436.1 [M+H]+。1H NMR (400MHz, DMSO) δ 9.63 (br s, 1H), 8.07 (br s, 2H), 7.76 (d, J=7.8Hz, 2H), 7.37 (d, J=7.9Hz, 2H), 4.50 (s, 2H), 4.30-4.18 (m, 1H), 4.03- 3.93 (m, 1H), 3.87-3.74 (m, 2H), 3.53-3.41 (m, 2H), 3.28-3.18 (m, 2H), 2.88-2.74 (m, 5H), 2.27-2.17 (m, 2H), 1.24 (t, J=7.6Hz, 3H).
Embodiment 358
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) benzyl) -2- (methylamino) acetamide
Step 1:(2- ((4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyrrole Pyridine -2- base) sulfenyl) methyl) benzyl) amino) -2- oxoethyl) (methyl) t-butyl carbamate
In room temperature, to N- (tertbutyloxycarbonyl)-sarcosine (22mg, 0.116mmol) in N, N- dimethyl formyl HATU (43mg, 0.113mmol) is added in solution in amine (0.75mL).Then the reaction mixture is stirred at room temperature 30 points 2- ((4- (amino methyl) benzyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) is added in clock at this time Pyridine -3,5- dimethoxy nitrile dihydrochloride (synthesis, 50mg, 0.101mmol are described in embodiment 71) and Et3N (0.044mL, 0.314mmol).Then the reaction mixture is continued to be stirred at room temperature, while monitors process with LCMS.After 2 hours, this is mixed It closes object filtering and the filtrate is purified into (Gilson, 30mm x 50mm Gemini column, NH with reversed-phase HPLC4OH modifying agent), it obtains To pure (2- ((4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) benzyl) amino) -2- oxoethyl) (methyl) t-butyl carbamate (35mg) is pale solid. LCMS m/z=592.4 [M+H]+。
Step 2:N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyrrole Pyridine -2- base) sulfenyl) methyl) benzyl) -2- (methylamino) acetamide
In room temperature, by (2- ((4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- Base) pyridine -2- base) sulfenyl) methyl) benzyl) amino) -2- oxoethyl) (methyl) t-butyl carbamate (25mg, 4M HCl (1.000mL, 4.0mmol) 0.042mmol) is suspended in the solution in dioxanes.By the reaction mixture in room Temperature stirring 1 hour.The reaction mixture is concentrated.By resulting materials be suspended in MeOH and with isopropylamine it is free-basing.This is mixed It closes object reversed-phase HPLC and purifies (Gilson, 30mm x 50mm Gemini column, NH4OH modifying agent), obtain N- (4- (((3,5- Dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) methyl) benzyl) -2- (first Base amino) acetamide (17mg) is white solid.LCMS m/z=492.4 [M+H]+。1H NMR (400MHz, DMSO-d6)δ Ppm 8.29 (t, J=6.08Hz, 1H), 7.30-7.37 (m, J=8.11Hz, 2H), 7.18-7.25 (m, J=8.11Hz, 2H), 4.47 (s, 2H), 4.27 (d, J=6.34Hz, 2H), 3.83-3.95 (m, 4H), 3.07 (s, 2H), 2.78 (q, J=7.60Hz, 2H), 2.62-2.66 (m, 2H), 2.45-2.49 (m, 2H), 2.25 (s, 3H), 2.24 (s, 3H), 1.88-1.96 (m, 2H), 1.22 (t, J=7.60Hz, 3H).1 proton does not measure.
Embodiment 359
2- ((3,5- dicyano -6- (6,7- dihydro -1H- [1,2,3] triazol [4,5-c] pyridine -5 (4H)-yl) -4- Ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides
The chloro- 6- of step 1:2- (6,7- dihydro -1H- [1,2,3] triazol [4,5-c] pyridine -5 (4H)-yl) -4- ethyl Pyridine -3,5- dimethoxy nitrile
In room temperature, exist to 4,5,6,7- tetrahydro -1H- [1,2,3] triazol [4,5-c] pyridines (0.659g, 5.31mmol) TEA (2.220mL, 15.92mmol) is added in agitating solution in DCM (50mL), the chloro- 4- ethylpyridine-of 2,6- bis- is then added 3,5- dimethoxy nitriles (describe synthesis, 1.2g, 5.31mmol in 3 step 2 of embodiment).The reaction mixture is stirred at 28 DEG C 16 hours.Water (10mL) is added and extracts the reaction mixture with DCM (10mL).Organic layer Na2SO4It dries and depressurizes dense Contracting, obtains crude product.By the crude material silica gel chromatography, uses the DCM solution of 5%MeOH as eluant, eluent, obtain The chloro- 6- of 2- (6,7- dihydro -1H- [1,2,3] triazol [4,5-c] pyridine -5 (4H)-yl) -4- ethylpyridine -3,5- dimethoxy nitrile (1g).LCMS m/z=314.0 [M+H]+。
Step 2:2- ((3,5- dicyano -6- (6,7- dihydro -1H- [1,2,3] triazol [4,5-c] pyridine -5 (4H) - Base) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides
To the chloro- 6- of 2- (6,7- dihydro -1H- [1,2,3] triazol [4,5-c] pyridine -5 (4H)-yl) -4- ethylpyridine - Thioacetic acid potassium is added in the agitating solution in n,N-Dimethylformamide (10mL) in 3,5- dimethoxy nitriles (1g, 3.19mmol) (0.546g, 4.78mmol).The reaction mixture is stirred at room temperature 30 minutes, methanesulfonic acid 2- amino -2- oxo-is then added 1- phenylethylester (describing synthesis, 0.731g, 3.19mmol in 3 step 5 of embodiment) and K2CO3(0.661g, 4.78mmol).The reaction mixture is stirred 16 hours at 28 DEG C.Water (100mL) is added and by the mixture ethyl acetate (2x 50mL) extraction.By combined organic layer Na2SO4It dries and is concentrated under reduced pressure, obtain crude product.By the crude material silicon Glue chromatogram purification, the DCM solution of 2-3%MeOH as eluant, eluent, obtain 2- ((3,5- dicyano -6- (6,7- dihydro -1H- [1, 2,3] triazol [4,5-c] pyridine -5 (4H)-yl) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides (93mg).LCMS M/z=445.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 14.71 (br s, 1H), 8.00 (br s, 1H), 7.58- 7.54 (d, J=7.1Hz, 2H), 7.42-7.30 (m, 4H), 5.64 (s, 1H), 5.03-4.96 (m, 2H) 4.14-4.07 (m, 2H) 2.86-3.02 (m, 2H), 2.85-2.75 (q, J=7.45Hz, 2H), 1.25 (t, J=7.56Hz, 3H).
Embodiment 360
2- ((4- amino -3- luorobenzyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyrrole Pyridine -3,5- dimethoxy nitrile
To 4- ethyl -2- sulfydryl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -3,5- dimethoxy nitrile (in reality Apply example 69, synthesis, 400mg, 1.062mmol described in step 1) and TEA (0.296mL, 2.123mmol) in DMF (4mL) Solution in be added (4- (bromomethyl) -2- fluorophenyl) t-butyl carbamate (323mg, 1.062mmol) in DMF (2mL) Solution.The reaction mixture is stirred at room temperature overnight.Reaction mixture RP-HPLC is purified (50-80% acetonitrile/ Water, 0.1%NH4The aqueous solution of OH), obtain pale solid.It is added into the dichloromethane solution (4.00mL) of above-mentioned solid TFA (1mL, 12.98mmol) is stirred 1 hour.The reaction mixture is concentrated, which is allocated between DCM and water, Then NH is used4OH alkalization.It separates each layer and is extracted twice with DCM water layer above.Combined organic matter is washed with brine, is used Na2SO4Dry, concentration obtains 2- ((4- amino -3- luorobenzyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- diaza cycloheptyl Alkane -1- base) pyridine -3,5- dimethoxy nitrile (208mg, 0.490mmol, 46% yield) is pale solid.LCMS m/z= 425.2[M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 1.22 (t, J=7.6Hz, 3H), 1.88-2.01 (m, 2H), 2.25 (s, 3H), 2.48 (br.s., 2H), 2.64-2.71 (m, 2H), 2.78 (q, J=7.6Hz, 2H), 3.85-3.99 (m, 4H), 4.36 (s, 2H), 5.18 (s, 2H), 6.70 (dd, J=9.5,8.2Hz, 1H), 6.91 (dd, J=8.2,1.9Hz, 1H), 7.03 (dd, J=12.4,1.8Hz, 1H).
Embodiment 361
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) -2- fluorophenyl) methylsulfonamides
At 0 DEG C, to 2- ((4- amino -3- luorobenzyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- Diazesuberane - 1- yl) pyridine -3,5- dimethoxy nitrile (synthesis, 50mg, 0.118mmol are described in embodiment 360) and TEA (0.033mL, It is molten in THF (1mL) that mesyl chloride (0.028mL, 0.353mmol) 0.236mmol) is added dropwise in the solution in THF (2mL) Liquid.The reaction mixture is stirred 40 minutes.The reaction mixture is concentrated and purified with RP-HPLC (5-50% acetonitrile/water, 0.1%NH4The aqueous solution of OH), obtain N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberanes - 1- yl) pyridine -2- base) sulfenyl) methyl) -2- fluorophenyl) methylsulfonamides (12mg, 0.024mmol, 20% yield), for ash White foam solid.LCMS m/z=503.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 1.21-1.25 (m, 3H), 1.99 (br.s., 2H), 2.28-2.44 (m, 3H), 2.50 (br.s., 2H), 2.79 (q, J=7.5Hz, 4H), 3.02 (s, 3H), 3.77-4.04 (m, 4H), 4.50 (s, 2H), 7.24 (dd, J=8.4,1.8Hz, 1H), 7.30-7.39 (m, 2H), 9.70 (br.s., 1H).
Embodiment 362
N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) -2- fluorophenyl) acetamide
At 0 DEG C, to 2- ((4- amino -3- luorobenzyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- Diazesuberane - 1- yl) pyridine -3,5- dimethoxy nitrile (synthesis, 60mg, 0.141mmol are described in embodiment 360) and TEA (0.039mL, The solution of chloroacetic chloride (0.030mL, 0.424mmol) in THF (1mL) 0.283mmol) is added dropwise in the solution in THF (2mL) (very slow addition, monitored by LCMS).The reaction mixture is stirred 2 hours.The reaction mixture is concentrated and uses RP- HPLC purifies (30-50% acetonitrile/water, 0.1%NH4The aqueous solution of OH), obtain N- (4- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) methyl) -2- fluorophenyl) acetamide (42mg, 0.090mmol, 64% yield), it is canescence vitreous solid.LCMS m/z=467.2 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 1.22 (t, J=7.6Hz, 3H), 1.86-1.98 (m, 2H), 2.07 (s, 3H), 2.23 (s, 3H), 2.49- 2.45 (m, 2H), 2.59-2.65 (m, 2H), 2.78 (q, J=7.6Hz, 2H), 3.82-3.94 (m, 4H), 4.48 (s, 2H), 7.18 (dd, J=8.4,1.5Hz, 1H), 7.28 (dd, J=11.7,1.8Hz, 1H), 7.83 (t, J=8.2Hz, 1H), 9.74 (s, 1H).
Embodiment 363:
2- (4- amino piperidine -1- base) -4- ethyl -6- (((1- (2- hydroxyethyl) -1H- pyrazoles -4- base) methyl) sulphur Base) pyridine -3,5- dimethoxy nitrile
Step 1:2- (4- (((6- (4- ((tertbutyloxycarbonyl) amino) piperidin-1-yl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) sulfenyl) methyl) -1H- pyrazol-1-yl) methyl acetate
In room temperature, to 2- (4- (hydroxymethyl) -1H- pyrazol-1-yl) methyl acetate (600mg, 3.53mmol) in dichloro TEA (0.983mL, 7.05mmol) is added in solution in methane (12mL), MsCl (0.412mL, 5.29mmol) then is added And it is stirred 20 minutes in the temperature.DCM, TEA are distilled in room temperature, obtain crude 2- (4- (((methyl sulphonyl) oxygroup) Methyl) -1H- pyrazol-1-yl) methyl acetate (550mg).In room temperature, to (1- (chloro- 3, the 5- dicyano -4- ethylpyridine -2- of 6- Base) piperidin-4-yl) t-butyl carbamate (synthesis, 500mg are described in embodiment 81, step 1) is in N, N- dimethyl methyl Thioacetic acid potassium (293mg, 2.56mmol) is added in solution in amide (10mL) and is stirred at room temperature 1 hour.Then it is added Thick material 2- (4- (((methyl sulphonyl) oxygroup) methyl) -1H- pyrazoles-is then added in potassium carbonate (0.354g, 2.56mmol) 1- yl) solution of the methyl acetate (478mg) in DMF.The reaction is stirred at room temperature 2 hours.By the reaction with water (200mL) It is quenched and ethyl acetate (300mL) is used to extract.By organic layer anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure.By the crude material Material obtains 2- (4- (((3,5- dicyan by silica gel chromatography (100-200 mesh is eluted with the DCM solution of 5%MeOH) Base -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) methyl) -1H- pyrazol-1-yl) methyl acetate (500mg). LCMS m/z=540.4 [M+H]+。
Step 2:(1- (3,5- dicyano -4- ethyl -6- (((1- (2- hydroxyethyl) -1H- pyrazoles -4- base) methyl) sulphur Base) pyridine -2- base) piperidin-4-yl) t-butyl carbamate
In room temperature, to 2- (4- (((6- (4- ((tertbutyloxycarbonyl) amino) piperidin-1-yl) -3,5- dicyano -4- ethyl Pyridine -2- base) sulfenyl) methyl) -1H- pyrazol-1-yl) methyl acetate (500mg) in the solution in methanol (10mL) in batches plus Enter NaBH4(175mg, 4.63mmol) and the reaction mixture is stirred at room temperature 16 hours.The reaction mixture water is dilute It releases, is neutralized and be extracted with dichloromethane with dilute HCl.By organic layer anhydrous Na2SO4It dries, filters and the filtrate is concentrated, obtain To (1- (3,5- dicyano -4- ethyl -6- (((1- (2- hydroxyethyl) -1H- pyrazoles -4- base) methyl) sulfenyl) pyridine -2- base) Piperidin-4-yl) t-butyl carbamate (500mg).LCMS m/z=512.1 [M+H]+。
Step 3:2- (4- amino piperidine -1- base) -4- ethyl -6- (((1- (2- hydroxyethyl) -1H- pyrazoles -4- base) first Base) sulfenyl) pyridine -3,5- dimethoxy nitrile
In room temperature, to (1- (3,5- dicyano -4- ethyl -6- (((1- (2- hydroxyethyl) -1H- pyrazoles -4- base) first Base) sulfenyl) pyridine -2- base) piperidin-4-yl) stirring of the t-butyl carbamate (500mg) in 1,4- dioxanes (4mL) be molten HCl (4M in Isosorbide-5-Nitrae-dioxanes, 1.222mL, 4.89mmol) is added in liquid and is stirred at room temperature 1 hour.The reaction is mixed Object is concentrated under reduced pressure, which is diluted with water (20mL), is neutralized with saturated sodium bicarbonate aqueous solution and uses acetic acid second Ester (3x 50mL) extraction.Combined organic layer is washed with salt water (30mL), uses anhydrous Na2SO4It dries, filters and depressurizes dense Contracting.Raw product preparative-HPLC is purified, 2- (4- amino piperidine -1- base) -4- ethyl -6- (((1- (2- hydroxyl is obtained Ethyl) -1H- pyrazoles -4- base) methyl) sulfenyl) pyridine -3,5- dimethoxy nitrile (90mg) is pale solid.LCMS m/z= 412.2[M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.68 (s, 1H), 7.40 (s, 1H), 4.42 (br d, J= 13.59Hz 2H), 4.33 (s, 2H), 4.08 (t, J=5.70Hz, 2H), 3.69 (t, J=5.59Hz, 2H), 3.36 (br s, 2H), 2.98-2.87 (m, 1H), 2.77 (q, J=7.60Hz, 2H), 1.85 (br dd, J=12.72,3.29Hz, 2H), 1.38- 1.27 (m, 2H), 1.22 (t, J=7.67Hz, 3H).Three protons do not measure.
Embodiment 364:
2- ((6- (((1H- imidazoles -2- base) methyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides
Step 1:2- (((1H- imidazoles -2- base) methyl) (methyl) amino) chloro- 4- ethylpyridine -3,5- dimethoxy nitrile of -6-
At 0 DEG C, to 1- (1H- imidazoles -2- base)-N- methyl methylamine (123mg, 1.106mmol) at methylene chloride (15mL) In agitating solution in be added triethylamine (0.308mL, 2.212mmol), the chloro- 4- ethylpyridine -3,5- of 2,6- bis- is then added Dimethoxy nitrile (describes synthesis, 250mg, 1.106mmol in 3 step 2 of embodiment).The reaction mixture is stirred 30 at 0 DEG C Minute.The reaction mixture is quenched with water (5.0mL) and is extracted with methylene chloride (50mL).Organic layer saturated salt is water-soluble Liquid (10mL) washing, uses Na2SO4It dries, filters and is concentrated under reduced pressure, obtain 2- (((1H- imidazoles -2- base) methyl) (methyl) ammonia Base) the chloro- 4- ethylpyridine -3,5- dimethoxy nitrile (250mg) of -6-.LCMS m/z=301.0 [M+H]+。
Step 2:2- ((6- (((1H- imidazoles -2- base) methyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine - 2- yl) sulfenyl) -2- phenyl-acetamides
In room temperature, to 2- (((1H- imidazoles -2- base) methyl) (methyl) amino) chloro- 4- ethylpyridine -3, the 5- diformazan of -6- Thioacetic acid potassium (190mg, 1.663mmol) is added in nitrile (250mg) in the solution in n,N-Dimethylformamide (5.0mL). The reaction mixture is stirred 2 hours at 28 DEG C.Then in 0 DEG C of addition potassium carbonate (230mg, 1.663mmol) and methanesulfonic acid 2- Amino -2- oxo -1- phenylethylester (describing synthesis, 191mg, 0.831mmol in 3 step 5 of embodiment).By the reaction Mixture stirs 16 hours at 28 DEG C.The reaction mixture is diluted with ice cold water (50mL) and with ethyl acetate (2x 100mL) Extraction.Combined organic layer is washed with water (100mL), uses anhydrous Na2SO4It is dried, filtered and concentrated.The crude material is used Column chromatography purifying (neutral alumina is eluted with the DCM solution of 2%MeOH), obtains 2- ((6- (((1H- imidazoles -2- base) methyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides (102mg) are light brown Solid.LCMS m/z=432.2 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 12.05 (br s, 1H), 8.17 (s, 1H), 7.50-7.23 (m, 6H), 7.04 (br s, 2H), 5.51 (s, 1H), 5.23 (d, J=16.00Hz, 1H), 4.84 (d, J= 15.9Hz, 1H), 3.41 (s, 3H), 2.78 (q, J=7.5Hz, 2H), 1.21 (t, J=7.67Hz, 3H).
Embodiment 365:
2- ((6- (((1H- imidazoles -5- base) methyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides
Step 1:2- (((1H- imidazoles -5- base) methyl) (methyl) amino) chloro- 4- ethylpyridine -3,5- dimethoxy nitrile of -6-
At 0 DEG C, to 1- (1H- imidazoles -5- base)-N- methyl methylamine (0.492g, 4.42mmol) at methylene chloride (50mL) In agitating solution in be added triethylamine (1.233mL, 8.85mmol), the chloro- 4- ethylpyridine -3,5- bis- of 2,6- bis- is then added Formonitrile HCN (describes synthesis, 1g, 4.42mmol in 3 step 2 of embodiment).The reaction mixture is stirred 30 minutes at 0 DEG C.It will The reaction mixture is quenched with water (5.0mL) and is extracted with methylene chloride (50mL).By organic layer saturated brine solution (10mL) washing, uses Na2SO4It dries, filters and is concentrated under reduced pressure, obtain 2- (((1H- imidazoles -5- base) methyl) (methyl) amino) - The chloro- 4- ethylpyridine -3,5- dimethoxy nitrile (600mg) of 6-.LCMS m/z=301.0 [M+H]+。
Step 2:2- ((6- (((1H- imidazoles -5- base) methyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine - 2- yl) sulfenyl) -2- phenyl-acetamides
In room temperature, to 2- (((1H- imidazoles -5- base) methyl) (methyl) amino) chloro- 4- ethylpyridine -3, the 5- diformazan of -6- Nitrile (600mg) be added in the agitating solution in n,N-Dimethylformamide (15mL) thioacetic acid potassium (456mg, 3.99mmol).The reaction mixture is stirred at room temperature 2 hours.Then in 28 DEG C of addition potassium carbonate (551mg, 3.99mmol) With methanesulfonic acid 2- amino -2- oxo -1- phenylethylester (describe synthesis in 3 step 5 of embodiment, 457mg, 1.995mmol).The reaction mixture is stirred 16 hours at 28 DEG C.The reaction mixture is diluted with cold water and uses acetic acid second Ester (2x 60mL) extraction.Combined organic layer is dried, filtered and is concentrated under reduced pressure with sodium sulphate, brown glue is obtained.This is crude Compound reverse phase C-18 column chromatography is purified, and purifies instrument (solution of 20-25% acetonitrile) using Grace Reveleris.It will The product is further purified with preparative HPLC and product fraction is concentrated.Surplus material is diluted with water, stirs 10 minutes, obtains To precipitating and filtering, 2- ((6- (((1H- imidazoles -5- base) methyl) (methyl) amino) -3,5- dicyano -4- ethyl pyrrole is obtained Pyridine -2- base) sulfenyl) -2- phenyl-acetamides (160mg) are pale solid.LCMS m/z=432.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 12.04 (br s, 1H) 8.02 (br s, 1H) 7.68-7.60 (m, 1H) 7.46 (dd, J= 7.78,1.43Hz, 2H) 7.40-7.14 (m, 4H), 7.12 (s, 1H), 5.64 (s, 1H), 5.05 (d, J=15.35Hz, 1H), 4.79 (d, J=15.35Hz, 1H), 3.34 (s, 3H), 2.76 (q, J=7.53Hz, 2H), 1.20 (t, J=7.56Hz, 3H).
Embodiment 366:
(2R) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- second Yl pyridines -2- base) piperidin-4-yl) propionamide, hydrochloride
Step 1:((2R) -1- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- Ethylpyridine -2- base) piperidin-4-yl) amino) -1- oxo propyl- 2- yl) t-butyl carbamate
In room temperature, to (R) -2- ((tertbutyloxycarbonyl) amino) propionic acid (198mg, 1.049mmol) in methylene chloride Diisopropylethylamine (0.561mL, 3.15mmol) is added in agitating solution in (5mL).By the reaction mixture in Xiang Tongwen Degree stirring 5 minutes, be then added propylphosphonic anhydride (0.936mL, 1.573mmol) and 2- ((6- (4- amino piperidine -1- base) -3, 5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides, hydrochloride (describes conjunction in 286 step 2 of embodiment It is stirred 16 hours at 500mg, 1.049mmol) and by the reaction mixture.By the reaction mixture with methylene chloride (100mL) Dilution, is then washed with cold water (100mL).By organic layer Na2SO4It dries, filters and is concentrated under reduced pressure, obtain residue, by it It is ground with petroleum ether (100mL), obtains ((2R) -1- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- Dicyano -4- ethylpyridine -2- base) piperidin-4-yl) amino) -1- oxo propyl- 2- yl) t-butyl carbamate (500mg), For pale solid.LCMS m/z=592.1 [M+H]+。
Step 2:(2R) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyan Base -4- ethylpyridine -2- base) piperidin-4-yl) propionamide, hydrochloride
At 5 DEG C, to ((2R) -1- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano - 4- ethylpyridine -2- base) piperidin-4-yl) amino) -1- oxo propyl- 2- yl) t-butyl carbamate (500mg) 1,4- bis- dislike HCl (Isosorbide-5-Nitrae-dioxane of 4M, 1.955mL, 7.82mmol) is added in agitating solution in alkane (15mL).Gained is reacted Mixture is stirred at room temperature 8 hours.The reaction mixture is diluted with ether (50mL), is precipitated and is stirred at room temperature 10 points Clock.It is washed by the solid of precipitation by filtered on buchner funnel and by solid filter cake with excess diethyl ether.By the solid triturated under ether (200mL), it is dry, it is then lyophilized, obtains (2R) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulphur Base) -3,5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl) propionamide, hydrochloride (360mg).LCMS m/z=492.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.51 (br s, 1H), 8.15 (br s, 3H), 7.95 (br s, 1H), 7.53 (d, J=7.23Hz, 2H), 7.42-6.99 (m, 4H), 5.61-5.50 (m, 1H), 4.42 (br dd, J=13.37, 4.17Hz, 2H), 4.04-3.72 (m, 2H), 3.50-3.35 (m, 2H), 2.76 (q, J=7.6Hz, 2H) 1.98-1.82 (m, 2H), 1.60-1.40 (m, 2H), 1.38 (d, J=6.8Hz, 3H), 1.21 (t, J=7.6Hz, 3H).
Embodiment 367:
N- (4- (((3,5- dicyano -4- ethyl -6- (3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) methyl) Benzyl) -2- hydroxyl acetamide
Step 1:(4- (((3,5- dicyano -4- ethyl -6- (3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) first Base) benzyl) t-butyl carbamate
In room temperature, to the chloro- 4- ethyl -6- of 2- (3- hydroxyl pyrrolidine -1- base) pyridine -3,5- dimethoxy nitrile (in embodiment 370, synthesis, 1g are described in step 1) thioacetic acid potassium is added in the solution in n,N-Dimethylformamide (20mL) (0.392g, 3.43mmol) and the reaction mixture is stirred at room temperature 2 hours.Then be added potassium carbonate (0.949g, 6.87mmol) and 4- (chloromethyl) the benzylcarbamate tert-butyl ester (900mg, 3.52mmol) and the mixture is stirred at room temperature 1 hour.The reaction mixture is diluted with water (100mL) and is extracted with ethyl acetate (2x 100mL).By combined organic layer With cold water (2x 100mL), anhydrous Na is used in saline solution (100mL) washing2SO4It is dried, filtered and concentrated.By the crude material With silica gel column purification (100-200 mesh is eluted with the DCM solution of 3%MeOH), 4- (((3,5- dicyano -4- ethyl -6- are obtained (3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) methyl) the benzylcarbamate tert-butyl ester (500mg), it is solid for canescence Body.LCMS m/z=494.1 [M+H]+。
Step 2:2- ((4- (amino methyl) benzyl) sulfenyl) -4- ethyl -6- (3- hydroxyl pyrrolidine -1- base) pyridine -3, 5- dimethoxy nitrile, hydrochloride
Under 0 DEG C of nitrogen, to 4- (((3,5- dicyano -4- ethyl -6- (3- hydroxyl pyrrolidine -1- base) pyridine -2- base) Sulfenyl) methyl) HCl (4M is added in the benzylcarbamate tert-butyl ester (500mg) in the agitating solution in 1,4- dioxanes (5mL) Isosorbide-5-Nitrae-dioxane, 5mL, 20.00mmol).The reaction mixture is stirred at room temperature 3 hours.By the reaction mixture Vacuum concentration, is then washed and is dried with ether, obtain 2- ((4- (amino methyl) benzyl) sulfenyl) -4- ethyl -6- (3- hydroxyl Pyrrolidin-1-yl) pyridine -3,5- dimethoxy nitrile, hydrochloride (440mg), is pale solid.LCMS m/z=394.1 [M+H ]+。
Step 3:N- (4- (((3,5- dicyano -4- ethyl -6- (3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) Methyl) benzyl) -2- hydroxyl acetamide
Under 0 DEG C of nitrogen, to 2- ((4- (amino methyl) benzyl) sulfenyl) -4- ethyl -6- (3- hydroxyl pyrrolidine -1- Base) pyridine -3,5- dimethoxy nitrile, hydrochloride (440mg), 2- hydroxyacetic acid (146mg, 1.924mmol) and HATU (366mg, 0.962mmol) in the agitating solution in n,N-Dimethylformamide (10mL) be added diisopropylethylamine (0.504mL, 2.89mmol).The reaction mixture is stirred at room temperature 5 hours.The reaction mixture down to ice cold water (50mL) and is used into second Acetoacetic ester (2x 50mL) extraction.By combined organic layer saturation NH4Cl (2x 50mL), water (2x 50mL) and saturated brine Solution (50mL) washing, then uses anhydrous Na2SO4It dries, filters and is concentrated, obtain black colloidal solid.The crude material is used Silica gel column purification (100-200 mesh is eluted with the DCM solution of 3%MeOH), obtains N- (4- (((3,5- dicyano -4- ethyl -6- (3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) methyl) benzyl) -2- hydroxyl acetamide (230mg), it is solid for canescence Body.LCMS m/z=452.2 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm8.29-8.17 (m, 1H), 7.34 (d, J= 8.11Hz, 2H), 7.22 (d, J=8.11Hz, 2H), 5.54-5.37 (m, 1H), 5.11 (d, J=3.29Hz, 1H), 4.49 (s, 2H), 4.40 (br s, 1H), 4.27 (d, J=6.14Hz, 2H), 4.24-3.84 (m, 5H), 3.81-3.66 (m, 1H) 2.75 (q, J=7.50Hz, 2H) 2.14-1.83 (m, 2H), 1.21 (t, J=7.67Hz, 3H).
Embodiment 368:
4- (2- amino -1- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyrrole Pyridine -2- base) sulfenyl) -2- oxoethyl) benzamide
Step 1:4- (cyano ((trimethyl silyl) oxygroup) methyl) benzonitrile
To 4- formylbenzonitrile (6.55g, 49.9mmol) and potassium phthalimide (potassium 1,3- Dioxoisoindolin-2-ide) in the mixture of (1.156g, 6.24mmol) be added trimethylsilyl cyanide (5.95g, 59.9mmol).The mixture is stirred at room temperature 2 hours.The reaction is quenched by the way that water (40mL) is added, then uses acetic acid second Ester (2x 100mL) extraction.Combined organic layer is washed with water (25mL), uses Na2SO4It dries and concentrates, obtains 4- (cyano ((trimethyl silyl) oxygroup) methyl) benzonitrile (8.2g, 35.6mmol, 71% yield) is yellow solid.1H NMR (400MHz, CDCl3) δ 7.75 (d, J=8.3Hz, 2H), 7.63 (d, J=8.3Hz, 2H), 5.57 (s, 1H), 0.30 (s, 9H).
Step 2:4- (cyano (hydroxyl) methyl) benzonitrile
To stirred in air at room temperature 4- (cyano ((trimethyl silyl) oxygroup) methyl) benzonitrile (8.2g, It 35.6mmol) is blasted in the solution in Isosorbide-5-Nitrae-dioxanes (50mL) HCl (gas), continues 30 minutes.By the reaction mixture It is stirred at room temperature overnight.The mixture is concentrated in vacuo, obtain 4- (cyano (hydroxyl) methyl) benzonitrile (1.9g, 12.01mmol, 34% yield), it is gray solid.1H NMR (400MHz, DMSO) δ 7.81 (d, J=8.3Hz, 2H), 7.63 (d, J= 8.2Hz, 2H), 6.33 (d, J=4.9Hz, 1H), 4.97 (d, J=4.9Hz, 1H).
Step 3:4- (2- amino -1- hydroxyl -2- oxoethyl) benzamide
To 4- (cyano (hydroxyl) methyl) benzonitrile (680mg, 4.30mmol) stirred under nitrogen at room temperature in tetrahydrofuran Be added in solution and water (5mL) in (15mL) acetamide (1524mg, 25.8mmol) and palladium chloride (II) (152mg, 0.86mmol).The reaction mixture is stirred at room temperature overnight.The mixture is concentrated in vacuo, by residue DCM (100mL) dissolution.The solid is filtered out and is washed with DCM (2x 20mL).The filtrate is concentrated, is then dried in vacuo, is obtained 4- (2- amino -1- hydroxyl -2- oxoethyl) benzamide (1.5g, 1.55mmol, 36% yield), is brown solid. LCMS m/z=195.2 [M+H]+。
Step 4: methanesulfonic acid 2- amino -1- (4- Carbamoylphenyl) -2- oxoethyl ester
To stirred in air at room temperature 4- (2- amino -1- hydroxyl -2- oxoethyl) benzamide (1.2g, Triethylamine (0.875g, 8.65mmol) and methane sulfonyl chloride 1.24mmol) are added in the suspension in methylene chloride (150mL) (0.708g, 6.18mmol).The reaction mixture is stirred at room temperature overnight.The mixture is concentrated, by the residue second Acetoacetic ester washs (3x 30mL), then (is eluted) with silica gel column purification with DCM/MeOH=1:0~5:1, obtains methanesulfonic acid 2- ammonia Base -1- (4- Carbamoylphenyl) -2- oxoethyl ester (0.8g, 0.91mmol, 74% yield) is yellowish solid. LCMS m/z=273.0 [M+H]+。
Step 5:4- (2- amino -1- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- Base) pyridine -2- base) sulfenyl) -2- oxoethyl) benzamide
To 4- ethyl -2- sulfydryl -6- (4- methyl-1, the 4- Diazesuberane -1- base) pyrrole stirred in air at room temperature Pyridine -3,5- dimethoxy nitrile (describing synthesis, 75mg, 0.25mmol in 69 step 1 of embodiment) is in n,N-Dimethylformamide In suspension in (9mL) be added methanesulfonic acid 2- amino -1- (4- Carbamoylphenyl) -2- oxoethyl ester (339mg, 0.37mmol) and triethylamine (50.4mg, 0.50mmol).The reaction mixture is stirred at room temperature overnight.The mixture is dense Contracting, which is washed and is filtered with DCM (20mL).The filter vacuum is concentrated, crude product is obtained, is used preparative HPLC column purifies and Me-CN/ trifluoroacetic acid 0.1% is used to elute.The reaction mixture is concentrated in vacuo and uses Na2CO3Solution adjusts pH To 13.It is dried in vacuo and washs the residue with water (3x 2mL), obtain 4- (2- amino -1- ((3,5- dicyano -4- second Base -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- oxoethyl) benzamide (65mg, 0.14mmol, 55% yield), it is white solid.LCMS m/z=478.1 [M+H]+。1H NMR (400MHz, methanol-d4)δ 7.92 (d, J=8.2Hz, 2H), 7.65 (d, J=8.3Hz, 2H), 5.61 (s, 1H), 4.02 (m, 4H), 2.93 (m, 2H), 2.89-2.68 (m, 4H), 2.43 (s, 3H), 2.16-2.06 (m, 2H), 1.32 (t, J=7.6Hz, 3H).Four protons are not surveyed It arrives.
Embodiment 369:
2- ((3,5- dicyano -4- cyclopropyl -6- (3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl Acetamide
The chloro- 4- cyclopropyl -6- of step 1:2- (3- hydroxyl pyrrolidine -1- base) pyridine -3,5- dimethoxy nitrile
At 0 DEG C, (conjunction is described in embodiment 4, step 2 to chloro- 4- cyclopropyl pyridine -3, the 5- dimethoxy nitrile of 2,6- bis- Three are added in the solution in methylene chloride (20mL) at 1g, 4.20mmol) and pyrrolidines -3- alcohol (0.366g, 4.20mmol) Ethamine (1.171mL, 8.40mmol).Gained mixture is stirred at room temperature 0.5 hour.The mixture is concentrated in vacuo.It should Residue silica gel chromatography (200g silica gel；With 50%EtOAc/ hexane elution), obtain chloro- 4- cyclopropyl -6- (the 3- hydroxyl of 2- Base pyrrolidin-1-yl) pyridine -3,5- dimethoxy nitrile (0.9g) is pale solid.LCMS m/z=289.0 [M+H]+。
Step 2:2- ((3,5- dicyano -4- cyclopropyl -6- (3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides
In room temperature, exist to the chloro- 4- cyclopropyl -6- of 2- (3- hydroxyl pyrrolidine -1- base) pyridine -3,5- dimethoxy nitrile (500mg) Thioacetic acid potassium (297mg, 2.60mmol) is added in solution in n,N-Dimethylformamide (20mL).By the mixture in room Temperature stirring 2 hours, then uses K2CO3(479mg, 3.46mmol) processing.After being stirred at room temperature 0.5 hour, methanesulfonic acid 2- ammonia is added Base -2- oxo -1- phenylethylester (synthesis, 595mg, 2.60mmol are described in embodiment 3, step 5) simultaneously mixes gained Object is closed to be stirred at room temperature overnight.The mixture is concentrated in vacuo, which is diluted with EtOAc (100mL).By the mixture It filters and the filter vacuum is concentrated.Remaining residue preparative-HPLC is purified, 2- ((3,5- dicyano -4- are obtained Cyclopropyl -6- (3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides (200mg) are yellow solid. LCMS m/z=419.8 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.90 (s, 1H), 7.55-7.49 (m, 2H), 7.42-7.26 (m, 4H), 5.60 (s, 1H), 5.13 (d, J=7.5,1H), 4.41 (s, 1H), 3.99-3.66 (m, 4H), 2.14- 2.06 (m, 1H), 2.03-1.87 (m, 2H), 1.17-1.08 (m, 2H), 1.02-0.88 (m, 2H).
Embodiment 370:
2- ((3,5- dicyano -4- ethyl -6- (3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl second Amide
The chloro- 4- ethyl -6- of step 1:2- (3- hydroxyl pyrrolidine -1- base) pyridine -3,5- dimethoxy nitrile
At 0 DEG C, to chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (synthesis is described in embodiment 3, step 2, 16.6g, 73.4mmol) and triethylamine (14.86g, 147mmol) 3- is added dropwise in the agitating solution in methylene chloride (200mL) Solution of ((t-butyldimethylsilyl) oxygroup) pyrrolidines (14.79g, 73.4mmol) in methylene chloride (200mL), Continue 5 minutes.The reaction mixture is stirred 15 hours at 20 DEG C.Water (100mL) and DCM are added into the mixture (100mL).It separates each layer and organic layer is dried and concentrated with anhydrous sodium sulfate to dry.By the residue silica gel chromatography (using 16%EtOAc/ petroleum ether solvent gradient elution), obtains the chloro- 4- ethyl -6- of 2- (3- hydroxyl pyrrolidine -1- base) pyridine -3, 5- dimethoxy nitrile (15.0g), is white solid.LCMS m/z=277.0 [M+H]+。
Step 2:2- ((3,5- dicyano -4- ethyl -6- (3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides
In room temperature, to the chloro- 4- ethyl -6- of 2- (3- hydroxyl pyrrolidine -1- base) pyridine -3,5- dimethoxy nitrile (1600mg, 5.78mmol) in the agitating solution in n,N-Dimethylformamide (20mL) be added thioacetic acid potassium (1321mg, 11.5mmol) the solution in n,N-Dimethylformamide (20mL) continues 1 minute.The reaction mixture is stirred 1 at 25 DEG C Hour.K is then added2CO3(1598mg, 11.56mmol) and methanesulfonic acid 2- amino -2- oxo -1- phenylethylester (are being implemented Example 3 describes synthesis, 1988mg, 8.67mmol in step 5) solution in n,N-Dimethylformamide (20mL).This is anti- Mixture is answered to stir 15 hours at 25 DEG C.The reaction mixture is quenched with water (100mL) and is allocated in ethyl acetate (100mL) Between hydrochloric acid (2M, 100mL).It separates each layer and organic layer anhydrous sodium sulfate is dried into (10g) and is concentrated in vacuo, obtain thick Product.The crude material is purified by preparative-HPLC, obtains 2- ((3,5- dicyano -4- ethyl -6- (3- hydroxypyrroles Alkane -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides (400mg) are faint yellow solid.LCMS m/z=407.8 [M+ H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.91 (s, 1H), 7.52 (d, J=7.6Hz, 2H), 7.45-7.25 (m, 4H), 5.61 (s, 1H), 5.13 (br.s, 1H), 4.42 (s, 1H), 4.02-3.70 (m, 4H), 2.75 (q, J=7.5Hz, 2H), 2.07- 1.86 (m, 2H), 1.20 (t, J=7.6Hz, 3H).
Embodiment 371:
N- (4- (((6- ((2- amino -2- oxoethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- Base) sulfenyl) methyl) benzyl) -2- hydroxyl acetamideStep 1:2- ((the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) (first Base) amino) acetamide
To chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile (6g, 26.5mmol) of 2,6- bis- in 0 DEG C of stirred under nitrogen in dichloro TEA (11.10mL, 80mmol) is added in solution in methane (100mL), 2- (methylamino) acetamide is then added (2.339g, 26.5mmol).The reaction mixture is stirred at room temperature 1 hour.By the reaction mixture with ice cold water (200mL) Dilution is extracted with DCM (2x200mL), combined organic layer is washed with saline solution (200mL) and uses anhydrous Na2SO4It is dry, Filtering and evaporation, obtain 2- ((chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-) (methyl) amino) acetamide (5g), are Pale solid.LCMS m/z=278.0 [M+H]+。
Step 2:4- (((6- ((2- amino -2- oxoethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine - 2- yl) sulfenyl) methyl) the benzylcarbamate tert-butyl ester
In room temperature, exist to 2- ((chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-) (methyl) amino) acetamide (1g) Thioacetic acid potassium (0.745g, 6.52mmol) is added in solution in n,N-Dimethylformamide (20mL) and mixes the reaction Object is stirred at room temperature 2 hours.Then, potassium carbonate (0.902g, 6.52mmol) and 4- (chloromethyl) benzylcarbamate uncle is added Simultaneously the reaction is stirred at room temperature 1 hour for butyl ester (1g, 3.91mmol).The reaction mixture is dilute with methylene chloride (100mL) It releases and is washed with water (2x 100mL) and saline solution (100mL).Organic layer passes through anhydrous Na2SO4It is dried, filtered and concentrated.It will The crude material is with silica gel column purification (100-200 mesh is eluted with the DCM solution of 4%MeOH).The fraction of collection is dry, it obtains To 4- (((6- ((2- amino -2- oxoethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) first Base) the benzylcarbamate tert-butyl ester (600mg) is pale solid.LCMS m/z=495.2 [M+H]+。
Step 3:2- ((6- ((4- (amino methyl) benzyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (first Base) amino) acetamide, hydrochloride
Under 0 DEG C of nitrogen, to 4- (((6- ((2- amino -2- oxoethyl) (methyl) amino) -3,5- dicyano -4- second Yl pyridines -2- base) sulfenyl) methyl) the benzylcarbamate tert-butyl ester (600mg) is in 1,4- dioxanes (10mL) in agitating solution It is added HCl (the 1,4- dioxane of 4M).The reaction mixture is stirred at room temperature 5 hours.The reaction mixture is concentrated, It is washed and is dried with ether, obtain 2- ((6- ((4- (amino methyl) benzyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) (methyl) amino) acetamide, hydrochloride (500mg), is pale solid.LCMS m/z=395.1 [M+H]+。
Step 4:N- (4- (((6- ((2- amino -2- oxoethyl) (methyl) amino) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) sulfenyl) methyl) benzyl) -2- hydroxyl acetamide
At 0 DEG C, to 2- ((6- ((4- (amino methyl) benzyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) amino) acetamide, hydrochloride (500mg), 2- hydroxyacetic acid (100mg, 1.309mmol) and HATU (415mg, 1.091mmol) in the solution in n,N-Dimethylformamide (20mL) be added diisopropylethylamine (0.571mL, 3.27mmol) and by the reaction mixture it is stirred at room temperature 5 hours.The reaction mixture is diluted with methylene chloride (100mL) And use NH4The saturated solution (2x 50mL) of Cl washs.Organic layer is washed and is used in combination with cold water (2x 100mL), salt water (100mL) Anhydrous Na2SO4It is dried, filtered and concentrated.By raw product silica gel column purification (100-200 mesh and with the DCM solution of 3%MeOH Elution), obtain N- (4- (((6- ((2- amino -2- oxoethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- Base) sulfenyl) methyl) benzyl) -2- hydroxyl acetamide (180mg) is pale solid.LCMS m/z=453.3 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.26-8.21 (m, 1H), 7.53 (br s, 1H), 7.33 (d, J=8.11Hz, 2H), 7.22 (d, J=8.2Hz, 2H), 7.16 (br s, 1H), 5.48-5.44 (m, 1H), 4.43 (s, 2H), 4.33 (s, 2H), 4.28 (d, J=6.14Hz, 2H), 3.85 (d, J=5.92Hz, 2H), 3.43 (s, 3H), 2.78 (q, J=7.67Hz, 2H), 1.22 (t, J=7.56Hz, 3H).
Embodiment 372:
(2R) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ring PropyIpyridine -2- base) piperidin-4-yl) propionamide
Step 1:(1- (the chloro- 3,5- dicyano -4- cyclopropyl pyridine -2- base of 6-) piperidin-4-yl) t-butyl carbamate
At 0 DEG C, to chloro- 4- cyclopropyl pyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (in 4 step 2 of embodiment describe synthesis, Piperidin-4-yl t-butyl carbamate (4.59g, 22.93mmol) 6g) is added in the solution in methylene chloride (100mL), so Triethylamine (3.20mL, 22.93mmol) is added afterwards.The reaction mixture is stirred 1 hour at 0 DEG C.The reaction mixture is existed The lower concentration of decompression, is diluted with water (100mL) and is extracted with ethyl acetate (2x 200mL).Organic layer is merged, anhydrous Na is used2SO4 It dries, filters and is concentrated under reduced pressure, obtain (1- (chloro- 3, the 5- dicyano -4- cyclopropyl pyridine -2- base of 6-) piperidin-4-yl) amino T-butyl formate (9g).LCMS m/z=402.2 [M+H]+。
Step 2:(1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyrrole Pyridine -2- base) piperidin-4-yl) t-butyl carbamate
In room temperature, to (1- (chloro- 3, the 5- dicyano -4- cyclopropyl pyridine -2- base of 6-) piperidin-4-yl) carbamic acid uncle Butyl ester (8g, 17.87mmol) be added in the solution in n,N-Dimethylformamide (80mL) thioacetic acid potassium (3.06g, 26.8mmol) and by the reaction mixture in mutually synthermal stirring 2 hours.In room temperature, be then added potassium carbonate (3.70g, 26.8mmol), methanesulfonic acid 2- amino -2- oxo -1- phenylethylester is then added and (describes conjunction in 3 step 5 of embodiment At 4.66g, 17.87mmol).The reaction mixture is stirred at room temperature 2 hours.The reaction mixture is quenched in cold water Simultaneously solid is precipitated in (200mL).The solid by filtration is collected, is washed with ether (50mL), is then dried, obtain (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine -2- base) piperidin-4-yl) amino T-butyl formate (7g).LCMS m/z=533.2 [M+H]+
Step 3:2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- Phenyl-acetamides, hydrochloride
At 0 DEG C, to (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyrrole Pyridine -2- base) piperidin-4-yl) t-butyl carbamate (6g) be added in the solution in 1,4- dioxanes (60mL) HCl (4M's Isosorbide-5-Nitrae-dioxane, 21.43mL, 86mmol) and stir the reaction mixture 4 hours at 25 DEG C.By the reaction mixture It is concentrated under reduced pressure, which is ground with ether (2x 200mL), filters and is dried in vacuo, obtain 2- ((6- (4- ammonia Phenylpiperidines -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- phenyl-acetamides, hydrochloride (4.5g), For pale solid.LCMS m/z=433.2 [M+H]+。
Step 4:((2R) -1- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- Cyclopropyl pyridine -2- base) piperidin-4-yl) amino) -1- oxo propyl- 2- yl) t-butyl carbamate
At 0 DEG C, to (R) -2- ((tertbutyloxycarbonyl) amino) propionic acid (179mg, 0.948mmol) in N, N- dimethyl methyl Be added in solution in amide (10mL) diisopropylethylamine (0.414mL, 2.371mmol) and HATU (451mg, 1.185mmol).By the reaction mixture in mutually synthermal stirring 10 minutes, 2- ((6- (4- amino piperazine then is added in room temperature Pyridine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- phenyl-acetamides, hydrochloride (450mg, 0.790mmol) and by the reaction mixture it is stirred at room temperature 3 hours.The reaction mixture is concentrated under reduced pressure, water is used (30mL) dilution is simultaneously extracted with ethyl acetate (2x 80mL).By combined organic layer anhydrous Na2SO4It dries, filters and depressurizes Concentration, obtains ((2R) -1- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl Pyridine -2- base) piperidin-4-yl) amino) -1- oxo propyl- 2- yl) t-butyl carbamate (400mg) is brown solid. LCMS m/z=604.2 [M+H]+。
Step 5:(2R) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyan Base -4- cyclopropyl pyridine -2- base) piperidin-4-yl) propionamide
At 0 DEG C, to ((2R) -1- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano - 4- cyclopropyl pyridine -2- base) piperidin-4-yl) amino) -1- oxo propyl- 2- yl) t-butyl carbamate (400mg) is in 1,4- bis- HCl (dioxane of 4M, 1.320mL, 5.28mmol) is added in solution in oxane (10mL) and by the reaction mixture It is stirred 4 hours at 25 DEG C.The reaction mixture is concentrated under reduced pressure, raw product is ground with ether (2x 20mL), filtering And it is concentrated.Crude material preparative-HPLC is purified, (2R) -2- amino-N- (1- (6- ((2- amino -2- oxo-is obtained 1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine -2- base) piperidin-4-yl) (185mg, 69% produces propionamide Rate), it is pale solid.LCMS m/z=504.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.88 (s, 1H), 7.74 (br d, J=7.89Hz, 1H), 7.56-7.49 (m, 2H), 7.42-7.28 (m, 4H), 5.52 (s, 1H), 4.39 (br t, J=12.17Hz, 2H), 3.95-3.84 (m, 1H), 3.33 (br s, 2H), 3.22 (s, 1H), 2.14-2.10 (m, 1H), 1.87 (br d, J=9.87Hz, 4H), 1.56-1.44 (m, 2H), 1.19-1.10 (m, 5H), 1.01-0.95 (m, 2H).
Embodiment 373:
2- ((6- ((2- amino-ethyl) (methyl) amino) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- Phenyl-acetamides, hydrochloride
Step 1:(2- ((the chloro- 3,5- dicyano -4- cyclopropyl pyridine -2- base of 6-) (methyl) amino) ethyl) amino first Tert-butyl acrylate
At 0 DEG C, to chloro- 4- cyclopropyl pyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (in 4 step 2 of embodiment describe synthesis, Triethylamine (1.652mL, 11.85mmol) 1.5g) is added in the agitating solution in methylene chloride (20mL), (2- is then added (methylamino) ethyl) t-butyl carbamate (1.032g, 5.92mmol).The reaction mixture is stirred at room temperature 2 hours. The reaction mixture is concentrated under reduced pressure, diluted with water (50mL) and is extracted with methylene chloride (2x 100mL).By merging Organic layer anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure, obtain (2- ((chloro- 3, the 5- dicyano -4- cyclopropyl pyridine -2- of 6- Base) (methyl) amino) ethyl) t-butyl carbamate (1.6g) is pale solid.LCMS m/z=376.1 [M+H]+。
Step 2:(2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyrrole Pyridine -2- base) (methyl) amino) ethyl) t-butyl carbamate
In room temperature, to (2- ((chloro- 3, the 5- dicyano -4- cyclopropyl pyridine -2- base of 6-) (methyl) amino) ethyl) amino T-butyl formate (1.3g) be added in the solution in n,N-Dimethylformamide (20mL) thioacetic acid potassium (0.552g, 4.83mmol) and by the reaction mixture in mutually synthermal stirring 2 hours.Then room temperature be added potassium carbonate (0.668g, 4.83mmol), methanesulfonic acid 2- amino -2- oxo -1- phenylethylester is then added and (describes conjunction in 3 step 5 of embodiment At 1.231g).The reaction mixture is stirred at room temperature 2 hours.(80mL), mistake is quenched in the reaction mixture in cold water Filter, is dried under reduced pressure.Ether (40mL) is added and stirs the mixture 15 minutes, then filters and is dried under reduced pressure, obtain (2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine -2- base) (methyl) ammonia Base) ethyl) t-butyl carbamate (850mg) is pale solid.LCMS m/z=507.2 [M+H]+。
Step 3:2- ((6- ((2- amino-ethyl) (methyl) amino) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulphur Base) -2- phenyl-acetamides, hydrochloride
At 0 DEG C, to (2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl Pyridine -2- base) (methyl) amino) ethyl) agitating solution of the t-butyl carbamate (700mg) in 1,4- dioxanes (10mL) Then the reaction mixture is stirred 4 at 25 DEG C by middle addition HCl (Isosorbide-5-Nitrae-dioxane of 4M, 3.20mL, 12.80mmol) Hour.The reaction mixture is concentrated under reduced pressure, which is ground with ether (2x 20mL), is filtered and true Sky is dry, obtains 2- ((6- ((2- amino-ethyl) (methyl) amino) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) - 2- phenyl-acetamides, hydrochloride (550mg), is pale solid.LCMS m/z=407.2 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.21 (br s, 1H), 8.10 (br s, 3H), 7.63-7.55 (m, 2H), 7.46-7.26 (m, 4H), 5.69 (s, 1H), 4.14-3.97 (m, 2H), 3.40 (s, 3H), 3.17-3.06 (m, 2H), 2.12 (tt, J=8.74,5.73Hz, 1H), 1.22-1.12 (m, 2H), 1.00-0.91 (m, 2H).
Embodiment 374:
2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl Pyridine -2- base) piperidin-4-yl) -2- methyl propanamide
Step 1:(1- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl Pyridine-2- base) piperidin-4-yl) amino)-2- methyl-1-oxo propyl- 2- yl) t-butyl carbamate
At 0 DEG C, to 2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) - 2- phenyl-acetamides, hydrochloride (describing synthesis, 400mg in 372 step 3 of embodiment) is in n,N-Dimethylformamide Be added in agitating solution in (30mL) diisopropylethylamine (0.261mL, 1.495mmol) and HATU (379mg, 0.997mmol).By the reaction mixture in mutually synthermal stirring 10 minutes, 2- ((tertbutyloxycarbonyl) ammonia then is added in room temperature Base) -2 Methylpropionic acid (152mg, 0.747mmol).The reaction mixture is stirred at room temperature 3 hours, then uses water (20mL) It dilutes and ethyl acetate (2x 50mL) is used to extract.By combined organic layer anhydrous Na2SO4It dries, filters and is concentrated, obtain (1- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine -2- base) piperidines - 4- yl) amino)-2- methyl-1-oxo propyl- 2- yl) t-butyl carbamate (500mg).1H NMR (400MHz, DMSO-d6)δ Ppm 8.16 (d, J=7.7Hz, 2H), 7.98 (s, 1H), 7.52 (d, J=7.3Hz, 2H), 7.40-7.29 (m, 4H), 5.54 (s, 1H), 4.54-4.93 (m, 2H), 4.25-4.18 (m, 1H), 4.04-3.97 (m, 2H), 3.57 (s, 6H), 3.43-3.37 (m, 2H), 2.16-2.08 (m, 1H), 1.87 (d, J=12.4Hz, 2H), 1.46 (s, 9H), 1.31-1.23 (m, 2H), 1.00- 0.94 (m, 2H).
Step 2:2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- Cyclopropyl pyridine -2- base) piperidin-4-yl) -2- methyl propanamide, hydrochloride
At 0 DEG C, to (1- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl Yl pyridines-2- base) piperidin-4-yl) amino)-2- methyl-1-oxo propyl- 2- yl) (700mg comes from t-butyl carbamate Combined two batches) in the agitating solution in Isosorbide-5-Nitrae-dioxanes (20mL) be added HCl (dioxane of 4M, 2.83mL, 11.33mmol) and by the reaction mixture at 25 DEG C stir 4 hours.The reaction mixture is concentrated under reduced pressure, by the remnants Object is ground with ether (2x 20mL), is filtered and is dried in vacuo.The residue is washed with ether (30mL) and pentane (30mL) It washs, is then dried in vacuo, obtain the material of 250mg, with 87.6% purity.By the material further progress preparative- HPLC purifying (uses 10mM ammonium bicarbonate soln, contain acetonitrile), obtains 2- amino-N- (1- (6- ((2- amino -2- oxo - 1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine -2- base) piperidin-4-yl) -2- methyl propanamide (120mg), It is pale solid.LCMS m/z=518.4 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.88 (s, 1H), 7.74 (br d, J=7.89Hz, 1H), 7.58-7.49 (m, 2H), 7.43-7.28 (m, 4H), 5.52 (s, 1H), 4.41 (br t, J=13.92Hz, 2H), 3.93-3.80 (m, 1H), 3.28-3.17 (m, 2H), 2.18-2.08 (m, 1H), 1.97-1.80 (m, 4H), 1.57-1.42 (m, 2H), 1.20-1.06 (m, 8H), 1.00-0.91 (m, 2H).
Embodiment 375:
4- (2- amino -1- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- oxo Ethyl) benzamide
(implementing to 2- chloro- 6- (the dimethylamino) -4- ethylpyridine -3,5- dimethoxy nitrile stirred in air at room temperature Describe synthesis, 59mg, 0.25mmol in 3 step 3 of example) be added in the solution in n,N-Dimethylformamide (9mL) it is thio Potassium acetate (28.7mg, 0.25mmol) and triethylamine (0.070mL, 0.50mmol).The reaction mixture is stirred at room temperature 1.5 Hour.Then methanesulfonic acid 2- amino -1- (4- Carbamoylphenyl) -2- oxoethyl ester (339mg, 0.37mmol) is added. The reaction mixture is stirred at room temperature overnight.The mixture is concentrated in vacuo, which is washed with DCM (3x 10mL). Solid preparative-HPLC is purified and (eluted with Me-CN/ trifluoroacetic acid 0.1%).By the fraction Na of collection2CO3Solution PH to 13 is adjusted, is then concentrated in vacuo, obtained solid is washed with water (3x 2mL), is then dried in vacuo, obtains 4- (2- ammonia Base -1- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- oxoethyl) benzamide (66mg, 0.16mmol, 64% yield), is white solid.LCMS m/z=409.1 [M+H]+。1H NMR (400MHz, first Alcohol-d4) δ ppm 7.91 (d, J=8.1Hz, 2H), 7.66 (d, J=7.4Hz, 2H), 5.69 (s, 1H), 3.41 (s, 6H), 2.91 (m, 2H), 1.31 (m, 3H).
Embodiment 376:
2- (6- (4- amino piperidine -1- base) -3- cyano -4- ethyl -5- picoline -2- base sulfenyl) -2- phenylacetyl Amine
Step 1:1- (the chloro- 5- cyano -4- ethyl -3- picoline -2- base of 6-) piperidin-4-yl t-butyl carbamate
It (is retouched in 293 step 2 of embodiment to the chloro- 4- ethyl -5- picoline -3- formonitrile HCN of 2,6- bis- being stirred at room temperature Stated synthesis, 1g, 4.65mmol) and triethylamine (1.411g, 13.95mmol) piperazine is added in the solution in acetonitrile (50mL) Pyridine -4- carbamate (1.117g, 5.58mmol).The reaction mixture is stirred overnight at 90 DEG C.This is organic It is mutually concentrated in vacuo, is washed with water (50mL) and saturated brine (25mL), extracted with methylene chloride (100mL), it is dry with sodium sulphate, It is filtered and concentrated in vacuo.Residue preparative-HPLC is purified, 1- (the chloro- 5- cyano -4- ethyl -3- methyl pyrrole of 6- is obtained Pyridine -2- base) piperidin-4-yl t-butyl carbamate (1g, 57%) is yellow solid.LCMS m/z=378.9 [M+H]+。
Step 2:1- (6- (2- amino -2- oxo -1- phenylethyl sulfenyl) -5- cyano -4- ethyl -3- picoline - 2- yl) piperidin-4-yl t-butyl carbamate
By (1- (the chloro- 5- cyano -4- ethyl -3- picoline -2- base of 6-) piperidin-4-yl) t-butyl carbamate (1g, 2.64mmol), 2- sulfydryl -2- phenyl-acetamides (describe synthesis in 276 step 1 of embodiment, 1.324g, 7.92mmol) and the solution of triethylamine (0.801g, 7.92mmol) in n,N-Dimethylformamide (35mL) is in 60 DEG C of microwaves It is stirred 12 hours in reactor.The mixture is concentrated in vacuo, yellow solid is obtained, it (is used into CH with silica gel purification2Cl2/ MeOH=20:1-10:1 elution), obtain 1- (6- (2- amino -2- oxo -1- phenylethyl sulfenyl) -5- cyano -4- ethyl -3- Picoline -2- base) piperidin-4-yl t-butyl carbamate (300mg, 22%) is pale solid.LCMS m/z= 509.9[M+H]+。
Step 3:2- (6- (4- amino piperidine -1- base) -3- cyano -4- ethyl -5- picoline -2- base sulfenyl) -2- benzene Yl acetamide
By (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -5- cyano -4- ethyl -3- picoline -2- Base) piperidin-4-yl) t-butyl carbamate (300mg, 0.59mmol) and 2,2,2- trifluoroacetic acids (67.1mg, 0.59mmol) Solution in methylene chloride (20mL) stirs 2 hours at 27 DEG C.By organic phase saturated sodium bicarbonate aqueous solution (25mL), Water (25mL) and saturated brine (25mL) washing, are dried, filtered and are concentrated in vacuo with sodium sulphate.The residue silicagel column is pure Change (being eluted with DCM:MeOH=10:1), obtains 2- (6- (4- amino piperidine -1- base) -3- cyano -4- ethyl -5- picoline - 2- base sulfenyl) -2- phenyl-acetamides (57mg, 24%).LCMS m/z=409.9 [M+H]+。1H NMR (400MHz, MeOD) δ Ppm 7.55 (d, J=6.9Hz, 2H), 7.47-7.26 (m, 3H), 5.58 (s, 1H), 3.72 (s, 2H), 3.08-2.87 (m, 3H), 2.80 (q, J=7.5Hz, 2H), 2.23 (s, 3H), 2.00 (d, J=12.0Hz, 2H), 1.57 (dd, J=19.7, 7.5Hz, 2H), 1.21 (t, J=7.6Hz, 3H).
Embodiment 377:
2- (4- (2- (dimethylamino) ethyoxyl) benzyl sulfenyl) -4- ethyl -6- (4- methyl-1,4- diaza cycloheptyl Alkane -1- base) pyridine -3,5- dimethoxy nitrile
Step 1:4- (2- (t-butyldimethylsilyl oxygroup) ethyoxyl) methyl benzoate
By 4-HBA methyl esters (3.0g, 19.72mmol) (2- bromine oxethyl) (tert-butyl) dimethyl silane The mixture of (5.66g, 23.66mmol) and cesium carbonate (7.71g, 23.66mmol) in n,N-Dimethylformamide (20mL) It stirs at 40-50 DEG C 2 hours, is then stirred 18 hours at 70-80 DEG C.Water (80mL) is added in the mixture.Gained is mixed Object is closed to be extracted with ethyl acetate (2x 30mL).Organic layer is washed with salt water (20mL), is then concentrated.The thick material is passed through Silica gel chromatography (petroleum ether solution of 0-10% ethyl acetate) obtains 4- (2- (t-butyldimethylsilyl oxygen Base) ethyoxyl) methyl benzoate (1.4g, 23% yield).1H NMR (400MHz, CDCl3) δ 8.00 (d, J=8.8Hz, 2H), 6.95 (d, J=8.8Hz, 2H), 4..12 (t, J=4.0Hz, 2H), 4.01 (t, J=4.0Hz, 2H), 3.91 (s, 3H), 0.93 (s, 9H), 0.12 (s, 6H).
Step 2:(4- (2- (t-butyldimethylsilyl oxygroup) ethyoxyl) phenyl) methanol
At 0-5 DEG C, to 4- (2- (t-butyldimethylsilyl oxygroup) ethyoxyl) methyl benzoate (850mg, 2.74mmol) in the solution in tetrahydrofuran (10mL) LiAlH is added portionwise4(208mg, 5.48mmol).By the mixture It stirs at 0-5 DEG C 1 hour, is then stirred 1 hour at 20-30 DEG C.Ethyl acetate (20mL) is added in the mixture and is then added Enter 5 to drip.Then the mixture is filtered and the filtrate is concentrated and uses the purification by flash chromatography (petroleum of 1-10% ethyl acetate Ethereal solution), obtain (4- (2- (t-butyldimethylsilyl oxygroup) ethyoxyl) phenyl) methanol (435mg, 56% yield) 。1H NMR (400MHz, DMSO) δ 7.22 (d, J=8.5Hz, 2H), 6.88 (d, J=8.5Hz, 2H), 5.05 (t, J=5.7Hz, 1H), 4.41 (d, J=5.7Hz, 2H), 4.00 (t, J=4.0Hz, 2H), 3.91 (t, J=4.0Hz, 2H), 0.88 (s, 9H), 0.07 (s, 6H).
Step 3:2- (4- (2- (t-butyldimethylsilyl oxygroup) ethyoxyl) benzyl sulfenyl) -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -3,5- dimethoxy nitrile
To 4- (2- ((t-butyldimethylsilyl) oxygroup) ethyoxyl) phenol (195mg, 0.73mmol), N- second Methane sulfonyl chloride is added in the mixture in methylene chloride (5mL) in base-N- isopropyl propyl- 2- amine (141mg, 1.09mmol) (92mg, 0.80mmol).The mixture is stirred 2 hours at 20-30 DEG C, obtains methanesulfonic acid 4- (2- ((tertbutyldimethylsilyl chloride Silylation) oxygroup) ethyoxyl) and phenylester crude solution.To 4- ethyl -2- sulfydryl -6- (4- methyl-1,4- diaza cycloheptyl Alkane -1- base) pyridine -3,5- dimethoxy nitrile (describing synthesis, 230mg, 0.76mmol in 69 step 1 of embodiment) and triethylamine Methanesulfonic acid 4- (2- ((tert-butyl two is added in (116mg, 1.15mmol) in the mixture in n,N-Dimethylformamide (10mL) Methyl silicane base) oxygroup) ethyoxyl) and phenylester above-mentioned solution.The mixture is stirred 16 hours at 20-30 DEG C.By water (40mL) is added in the mixture.Gained mixture is extracted with DCM (2x 20mL) and by combined organic layer water (20mL) Salt water (20mL) washing, is then concentrated.Thick material purification by flash chromatography (is used into petroleum ether: ethyl acetate=100:1-1:1 Elution), obtain 2- (4- (2- (t-butyldimethylsilyl oxygroup) ethyoxyl) benzyl sulfenyl) -4- ethyl -6- (4- first Base-Isosorbide-5-Nitrae-Diazesuberane -1- base) pyridine -3,5- dimethoxy nitrile (160mg, 37% yield).LCMS m/z=566.2 [M+H ]+。
Step 4:4- ethyl -2- (4- (2- hydroxyl-oxethyl) benzyl sulfenyl) -6- (4- methyl-1,4- diaza cycloheptyl Alkane -1- base) pyridine -3,5- dimethoxy nitrile
By 2- ((4- (2- ((t-butyldimethylsilyl) oxygroup) ethyoxyl) benzyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -3,5- dimethoxy nitrile (150mg, 0.27mmol) add to HCl solution (2M's MeOH solution, 5mL) and stir the mixture 1 hour at 20-30 DEG C.Mixture ammonium hydroxide is adjusted into pH to~7, then Concentration.The solid and DCM (30mL) are stirred 30 minutes, then filtered.By organic phase purification by flash chromatography (100%DCM To 5:1DCM:MeOH), 4- ethyl -2- (4- (2- hydroxyl-oxethyl) benzyl sulfenyl) -6- (4- methyl-1,4- diazacyclo is obtained Heptane -1- base) pyridine -3,5- dimethoxy nitrile (60mg, 50%).LCMS m/z=452.3 [M+H]+。
Step 5:2- (4- (2- (dimethylamino) ethyoxyl) benzyl sulfenyl) -4- ethyl -6- (4- methyl-1,4- phenodiazine Trioxepane -1- base) pyridine -3,5- dimethoxy nitrile
To 4- ethyl -2- ((4- (2- hydroxyl-oxethyl) benzyl) sulfenyl) -6- (4- methyl-1,4- Diazesuberane - 1- yl) pyridine -3,5- dimethoxy nitrile (55mg, 0.12mmol) and triethylamine (18.49mg, 0.18mmol) be at methylene chloride (5mL) In mixture in be added 4- methylbenzene -1- sulfonic acid chloride (25.5mg, 0.13mmol).The mixture is small in 20-30 DEG C of stirring 5 When, dimethylamine (0.6mL, 1.22mmol, 2M THF solution) then is added.The mixture is stirred at reflux 5 hours.By water (20mL) is added in the mixture.Gained mixture is extracted with DCM (2x 15mL).By combined organic layer with water (20mL) It washs with salt water (20mL), is then concentrated.By the solid, with purification by flash chromatography, (100%DCM to 10:1DCM:MeOH contains 5% NH4OH), 2- (4- (2- (dimethylamino) ethyoxyl) benzyl sulfenyl) -4- ethyl -6- (4- methyl-1,4- diazacyclo is obtained Heptane -1- base) pyridine -3,5- dimethoxy nitrile (35mg, 60% yield).LCMS m/z=479.2 [M+H]+。1H NMR (400MHz, CDCl3) δ ppm 7.31-7.25 (m, 2H), 6.89 (d, J=8.6Hz, 2H), 4.38 (s, 2H), 4.14 (t, J=5.5Hz, 2H), 4.04-3.99 (m, 2H), 3.96 (t, J=6.1Hz, 2H), 2.94 (q, J=7.6Hz, 2H), 2.85 (t, J=5.4Hz, 2H), 2.81-2.76 (m, 2H), 2.67-2.60 (m, 2H), 2.44 (s, 6H), 2.42 (s, 3H), 2.15-2.06 (m, 2H), 1.34 (t, J=7.6Hz, 3H).
Embodiment 378:
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- (4- (N- Methylsulfamoyl) phenyl) acetamide
Step 1:4- formyl-N-methyl benzsulfamide
Triethylamine (12.44mL, 89mmol) is added dropwise to 4- iodobenzene -1- sulfonic acid chloride (9g, 29.8mmol) and methylamine hydrochloric acid Salt (6.03g, 89mmol) stirs 10 hours in the agitating solution in DCM (200mL) and by the mixture at 20 DEG C.Then plus Enter water and organic layer is separated and uses anhydrous Na2SO4It dries, filters and is concentrated, obtain residue.By the residue, dicyano zinc The solution of (8.02g, 68.3mmol) and tetrakis triphenylphosphine palladium (1.579g, 1.37mmol) in DMF (100mL) is stirred at 95 DEG C It mixes 16 hours.After reaction cooling, which is concentrated, which is allocated between ethyl acetate and water. The organic phase is dried, filtered and concentrated with anhydrous sodium sulfate, which is purified with column chromatography, obtains raw product (4.7g).The product that will be obtained from preceding step, nickel (0.281g, 4.79mmol) and formic acid (60mL, 23.95mmol) mix Object is closed to stir 14 hours under 125 DEG C of nitrogen atmosphere.By the reaction it is cooling after, which is filtered and by the filter vacuum Concentration.The residue is purified with column chromatography.LCMS m/z=200.1 [M+H]+。
Step 2:4- (cyano ((trimethyl silyl) oxygroup) methyl)-N- methyl benzenesulfonamide
By 4- formyl-N-methyl benzsulfamide (2g, 10.0mmol), trimethylsilyl cyanide (50mL, 10.04mmol) It is stirred 24 hours with mixture of the potassium phthalimide (0.232g, 1.26mmol) in 20 DEG C.The mixture is concentrated, The residue is purified with column chromatography, obtains 4- (cyano ((trimethyl silyl) oxygroup) methyl)-N- methyl benzenesulfonamide (0.83g, 28% yield).LCMS m/z=321.0 [M+Na]+。
Step 3:2- hydroxyl -2- (4- (N- Methylsulfamoyl) phenyl) acetamide
At 20 DEG C, by 4- (cyano ((trimethyl silyl) oxygroup) methyl)-N- methyl benzenesulfonamide (914mg, 3.06mmol), palladium chloride (II) (109mg, 0.61mmol) and acetamide (1809mg, 30.6mmol) are at tetrahydrofuran (18mL) It is stirred 16 hours with the mixture in water (6.00mL).The reaction mixture is concentrated.The residue is purified with column chromatography, is obtained To 2- hydroxyl -2- (4- (N- Methylsulfamoyl) phenyl) acetamide (860mg, 89% yield).1H NMR (400MHz, DMSO- d6) δ ppm 7.73 (d, J=8.3Hz, 2H), 7.64 (d, J=8.3Hz, 2H), 7.49 (s, 1H), 7.41 (q, J=4.8Hz, 1H), 7.31 (s, 1H), 6.29 (d, J=4.8Hz, 1H), 4.96 (d, J=4.7Hz, 1H), 2.40 (d, J=4.8Hz, 3H).
Step 4: methanesulfonic acid 2- amino -1- (4- (N- Methylsulfamoyl) phenyl) -2- oxoethyl ester
MsCl (0.172mL, 2.21mmol) is added into 2- hydroxyl -2- (4- (N- Methylsulfamoyl) phenyl) acetamide (450mg, 1.84mmol) and triethylamine (0.770mL, 5.53mmol) are in the mixture of the stirring in methylene chloride (20mL). The mixture is stirred 5 hours at 0 DEG C.The mixture is concentrated, which is purified with column chromatography, obtains methanesulfonic acid 2- ammonia Base -1- (4- (N- Methylsulfamoyl) phenyl) -2- oxoethyl ester (345mg, 58% yield).LCMS m/z=345 [M+ Na]+。
Step 5:2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) -2- (4- (N- Methylsulfamoyl) phenyl) acetamide
By 4- ethyl -2- sulfydryl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -3,5- dimethoxy nitrile (in reality Apply in 69 step 1 of example and describe synthesis, 150mg, 0.50mmol), methanesulfonic acid 2- amino -1- (4- (N- Methylsulfamoyl) benzene Base) mixing of -2- oxoethyl ester (168mg, 0.52mmol) and triethylamine (0.208mL, 1.49mmol) in DMF (10mL) Object stirs 15 hours at 20 DEG C.The reaction mixture is concentrated, which is allocated between methylene chloride and water.This is had Machine mutually with anhydrous sodium sulfate drying, filtering and concentration, which is purified with column chromatography, obtains 2- ((3,5- dicyano -4- Ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (4- (N- Methylsulfamoyl) benzene Base) acetamide (61mg, 23%).LCMS m/z=528.0 [M+H]+。1H NMR (400MHz, CD3OD) 7.88 (d, J=of δ ppm 8.4Hz, 2H), 7.76 (d, J=8.4Hz, 2H), 4.04 (t, J=4.9Hz, 2H), 3.99 (t, J=6.0Hz, 2H), 2.93 (q, J=7.6Hz, 2H), 2.87 (dt, J=9.6,4.8Hz, 2H), 2.74 (d, J=6.7Hz, 2H), 2.56 (s, 3H), 2.46 (s, 3H), 2.15-2.07 (m, 2H), 1.32 (t, J=7.6Hz, 3H).
Embodiment 379:
4- ethyl -2- (4- methyl-1,4- Diazesuberane -1- base) -6- ((4- (methyl sulphonyl) benzyl) sulfenyl) Pyridine -3,5- dimethoxy nitrile
Step 1: methanesulfonic acid 4- (methyl sulphonyl) benzyl ester
At 0 DEG C, by MsCl (0.460mL, 5.91mmol) add to (4- (methyl sulphonyl) phenyl) methanol (1g, 5.37mmol) and triethylamine (2.245mL, 16.11mmol) is in the mixture of the stirring in DCM (25mL) and by the mixture It is stirred 5 hours at 0 DEG C.The reaction mixture is concentrated, which is allocated between methylene chloride and water.By the organic phase It is dried, filtered and is concentrated with anhydrous sodium sulfate, which is purified with column chromatography, obtain methanesulfonic acid 4- (methyl sulphonyl) benzyl Base ester (1.1g, 78% yield).LCMS m/z=287.0 [M+Na]+。
Step 2:4- ethyl -2- (4- methyl-1,4- Diazesuberane -1- base) -6- ((4- (methyl sulphonyl) benzyl Base) sulfenyl) pyridine -3,5- dimethoxy nitrile
By 4- ethyl -2- sulfydryl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -3,5- dimethoxy nitrile (in reality Apply in 69 step 1 of example and describe synthesis, 140mg, 0.46mmol), methanesulfonic acid 4- (methyl sulphonyl) benzyl ester (141mg, 0.53mmol) stirred 14 hours with the mixture of triethylamine (0.194mL, 1.39mmol) in DMF (20mL) at 20 DEG C.It should Reaction mixture concentration, which is allocated between methylene chloride and water.By organic phase anhydrous sodium sulfate drying, mistake Filter and vacuum concentration, which is purified with column chromatography, obtains 4- ethyl -2- (4- methyl-1,4- Diazesuberane -1- Base) -6- ((4- (methyl sulphonyl) benzyl) sulfenyl) pyridine -3,5- dimethoxy nitrile (70mg, 32% yield).LCMS m/z= 470.2[M+H]+。1H NMR (400MHz, CDCl3) δ ppm 7.90 (d, J=8.3Hz, 2H), 7.57 (d, J=8.2Hz, 2H), 4.48 (s, 2H), 3.98-3.90 (m, 2H), 3.87 (t, J=6.0Hz, 2H), 3.05 (s, 3H), 2.93 (q, J=7.6Hz, 2H), 2.75-2.66 (m, 2H), 2.62-2.53 (m, 2H), 2.38 (s, 3H), 2.05-1.98 (m, 2H), 1.33 (t, J= 7.6Hz, 3H).
Embodiment 380
2- (4- amino piperidine -1- base) -6- (((1- (2,3- dihydroxypropyl) -1H- pyrazoles -4- base) methyl) sulfenyl) - 4- ethylpyridine -3,5- dimethoxy nitrile, hydrochloride
Step 1:1- ((the amyl- 4- yl of 2,2- dimethyl -1,3- dioxane) methyl) -1H- pyrazoles -4- carboxylate:
In room temperature to (the amyl- 4- yl of 2,2- dimethyl -1,3- dioxanes) methanol (2.358g, 17.84mmol), triphen Base phosphine (9.36g, 35.7mmol) and DEAD (5.65mL, 35.7mmol) are slowly added in the solution in tetrahydrofuran (50mL) Then the reaction mixture is stirred at room temperature 16 hours for 1H- pyrazoles -4- carboxylate (2.5g, 17.84mmol).It should Crude compound (is eluted) with silica gel chromatography with 20%EtOAc/ petroleum ether, obtains 1- ((2,2- dimethyl -1,3- dioxies The amyl- 4- yl of heterocycle) methyl) -1H- pyrazoles -4- carboxylate (3g).LCMS m/z=255.3 [M+H]+。
Step 2:(1- ((the amyl- 4- yl of 2,2- dimethyl -1,3- dioxane) methyl) -1H- pyrazoles -4- base) methanol
1- is slowly added in the suspension in tetrahydrofuran (30mL) to LAH (0.896g, 23.60mmol) at 0 DEG C ((the amyl- 4- yl of 2,2- dimethyl -1,3- dioxane) methyl) -1H- pyrazoles -4- carboxylate (3g) is in tetrahydrofuran Then solution in (30mL) reaction mixture is stirred at room temperature 16 hours.The reaction is quenched with sodium sulphate saturated solution It goes out, is then stirred together with ethyl acetate (50mL).Organic layer is separated and is concentrated under reduced pressure, and obtains (1- ((2,2- dimethyl -1,3- The amyl- 4- yl of dioxane) methyl) -1H- pyrazoles -4- base) methanol (1.8g).LCMS m/z=213.1 [M+H]+。
Step 3:4- (bromomethyl) -1- ((the amyl- 4- yl of 2,2- dimethyl -1,3- dioxane) methyl) -1H- pyrazoles
In room temperature, to (1- ((the amyl- 4- yl of 2,2- dimethyl -1,3- dioxanes) methyl) -1H- pyrazoles -4- base) methanol Triphenylphosphine (1.204g, 4.45mmol) is added in the solution in methylene chloride (10mL) in (1.5g).Gained is reacted and is mixed Object stirs 5 minutes, then with two to three crowdes of addition CBr under room temperature under argon4(1.507g, 4.45mmol).The reaction is mixed Object is closed to be stirred at room temperature 2 hours.The reaction mixture is concentrated under reduced pressure, 4- (bromomethyl) -1- ((2,2- dimethyl-are obtained The amyl- 4- yl of 1,3- dioxane) methyl) -1H- pyrazoles (1.0g) is faint yellow semisolid.LCMS m/z=275.1 [M+H ]+。
Step 4:(1- (3,5- dicyano -6- (((1- ((the amyl- 4- yl of 2,2- dimethyl -1,3- dioxane) methyl) - 1H- pyrazoles -4- base) methyl) sulfenyl) -4- ethylpyridine -2- base) piperidin-4-yl) t-butyl carbamate
In room temperature, to (1- (chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-) piperidin-4-yl) the tertiary fourth of carbamic acid Ester (describing synthesis, 500mg in 81 step 1 of embodiment) is added in the solution in n,N-Dimethylformamide (3.0mL) Thioacetic acid potassium (148mg, 1.270mmol) simultaneously stirs gained mixture 2 hours mutually synthermal.In room temperature, to the reaction Potassium carbonate (181mg, 1.270mmol) and 4- (bromomethyl) -1- ((2,2- dimethyl -1,3- dioxanes are added in mixture Amyl- 4- yl) methyl) -1H- pyrazoles (688mg, 1.270mmol) and the mixture is stirred at room temperature 5 hours.The reaction is mixed Object is closed down in ice cold water (20mL) and with ethyl acetate (20mL) extraction.Organic layer is washed with water (50mL), uses sodium sulphate It dries and is concentrated under reduced pressure, obtain brown solid.By crude material silica gel chromatography (100-200 mesh, with 20%MeOH's The elution of DCM solution), obtain light tan solid.The solid is ground with ether (5mL), obtains (1- (3,5- dicyano -6- (((1- ((the amyl- 4- yl of 2,2- dimethyl -1,3- dioxane) methyl) -1H- pyrazoles -4- base) methyl) sulfenyl) -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) t-butyl carbamate (400mg) is light tan solid.LCMS m/z=582.5 [M+H]+。
Step 5:2- (4- amino piperidine -1- base) -6- (((1- (2,3- dihydroxypropyl) -1H- pyrazoles -4- base) methyl) Sulfenyl) -4- ethylpyridine -3,5- dimethoxy nitrile, hydrochloride
To (1- (3,5- dicyano -6- (((1- ((the amyl- 4- yl of 2,2- dimethyl -1,3- dioxane) methyl) -1H- pyrrole Azoles -4- base) methyl) sulfenyl) -4- ethylpyridine -2- base) piperidin-4-yl) and t-butyl carbamate (350mg) 1,4- bis- dislike HCl (4M in Isosorbide-5-Nitrae-dioxanes, 2.388mL, 9.55mmol) and small in 25 DEG C of stirrings 16 is added in solution in alkane (10mL) When.The reaction mixture is concentrated under reduced pressure and grinds raw product ether (2x 20mL), filters and is dried in vacuo. Thick material solid ether (50mL) and pentane (30mL) are washed and are then dried in vacuo, 2- (4- amino piperidine -1- is obtained Base) -6- (((1- (2,3- dihydroxypropyl) -1H- pyrazoles -4- base) methyl) sulfenyl) -4- ethylpyridine -3,5- dimethoxy nitrile, salt Hydrochlorate (220mg).LCMS m/z=442.4 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.20 (br s, 3H), 7.68 (s, 1H), 7.41 (s, 1H), 4.56 (br d, J=13.37Hz, 2H), 4.35-4.15 (m, 5H), 3.94 (br dd, J= 13.70,7.56Hz, 1H), 3.8-3.70 (m, 1H), 3.46-3.25 (m, 5H), 2.78 (q, J=7.38Hz, 2H), 2.14- 2.04 (m, 2H), 1.72-1.59 (m, 2H), 1.22 (t, J=7.67Hz, 3H).
Embodiment 381
2- ((3,5- dicyano -4- ethyl -6- (the fluoro- 1,4- Diazesuberane -1- base of 6-) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides
Step 1:4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) the fluoro- 1,4- Diazesuberane -1- t-butyl formate of -6-
At -20 DEG C, (conjunction is described in embodiment 3, step 2 to chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- The fluoro- Isosorbide-5-Nitrae of 6--Diazesuberane -1- formic acid uncle is added in the suspension in ethyl alcohol (1mL) at 100mg, 0.442mmol) Solution of the butyl ester (101mg, 0.464mmol) in ethyl alcohol (1mL).Then the reaction mixture is stirred 1 hour at -20 DEG C, The triethylamine (0.062mL, 0.442mmol) at -20 DEG C by 1 equivalent adds in the reaction mixture at this time.The reaction is mixed Object is warmed to 0 DEG C and is stirred overnight mutually synthermal.Then into the reaction mixture be added thioacetic acid potassium (76mg, 0.664mmol) and Et3N (0.154mL, 1.106mmol).Then the heterogeneous reaction mixture is warmed to 20 DEG C and at this Temperature stirs 7 hours.Into the reaction mixture be added methanesulfonic acid 2- amino -2- oxo -1- phenylethylester (101mg, 0.442mmol).The reaction is stirred 3.5 hours at 20 DEG C.After stirring 3.5 hours, additional ethyl alcohol (2mL) is added and will be warm Degree rises to 40 DEG C.The heterogeneous reaction mixture is for the weekend in 40 DEG C of stirrings.The reaction mixture is cooled to room temperature.It should Solid filters and uses ethyl alcohol and water washing.Then solid is dried in a vacuum drying oven, obtains 4- (6- ((2- amino -2- oxygen Generation -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) the fluoro- 1,4- Diazesuberane -1- formic acid of -6- The tert-butyl ester (109mg), is pale solid.It takes 25mg aliquot and purifies (Gilson, 30mm x with reversed-phase HPLC 50mm Gemini column, NH4OH modifying agent), obtain 4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyan Base -4- ethylpyridine -2- base) the fluoro- Isosorbide-5-Nitrae of -6--Diazesuberane -1- t-butyl formate (15mg) is white solid LCMS M/z=539.3 [M+H]+。
Step 2:2- ((3,5- dicyano -4- ethyl -6- (the fluoro- 1,4- Diazesuberane -1- base of 6-) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides
In room temperature, by 4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) the fluoro- Isosorbide-5-Nitrae of -6--Diazesuberane -1- t-butyl formate (84mg, 0.156mmol) is suspended in 4M HCl The solution of (1.500mL, 6.0mmol) in dioxanes.The reaction mixture is stirred at room temperature overnight, at this time mixes the reaction Close object concentration.By resulting materials be suspended in MeOH and with isopropylamine it is free-basing.The mixture is purified with reversed-phase HPLC (Gilson, 30mm x 50mm Gemini column, NH4OH modifying agent), obtaining 2-, (((6- is fluoro- by 3,5- dicyano -4- ethyl -6- Isosorbide-5-Nitrae-Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides (40mg) are white solid.LCMS m/ Z=439.2 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 7.95 (d, J=12.93Hz, 1H), 7.47-7.54 (m, 2H), 7.29-7.42 (m, 4H), 5.53 (d, J=2.53Hz, 1H), 4.87 (dd, J=5.20,18.12Hz, 1H), 4.48 (dt, J= 4.94,15.52Hz, 1H), 4.01-4.27 (m, 2H), 3.65-3.78 (m, 1H), 2.81-3.08 (m, 4H), 2.78 (q, J= 7.52Hz, 2H), 1.21 (t, J=7.60Hz, 3H).1 proton does not measure.
Embodiment 382
2- ((6- (4- amino -3,3- difluoropiperdin -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides
In room temperature, by (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) -3,3- difluoropiperdin -4- base) t-butyl carbamate (describe synthesis in embodiment 383,113mg, 0.203mmol) it is suspended in solution of the 4M HCl (2.000mL, 8.0mmol) in dioxanes.By the reaction mixture in room temperature It is stirred overnight.The reaction mixture is concentrated.By resulting materials be suspended in MeOH and with isopropylamine it is free-basing.By the mixture Purify (Gilson, 30mm x 50mm Gemini column, NH with reversed-phase HPLC4OH modifying agent), obtain 2- ((6- (amino -3 4-, 3- difluoropiperdin -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides (75mg), for white Solid.LCMS m/z=457.2 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.98 (s, 1H), 7.51-7.56 (m, 2H), 7.31-7.42 (m, 4H), 5.56 (s, 1H), 4.44-4.58 (m, 1H), 4.10-4.26 (m, 1H), 3.76-3.91 (m, 1H), 3.52-3.64 (m, 1H), 3.15-3.29 (m, 1H), 2.78 (q, J=7.60Hz, 2H), 1.90-2.01 (m, 1H), 1.83 (br.s., 2H), 1.63 (d, J=9.12Hz, 1H), 1.21 (t, J=7.73Hz, 3H).
Embodiment 383
(1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) - 3,3- difluoropiperdin -4- base) t-butyl carbamate
At -20 DEG C, (conjunction is described in embodiment 3, step 2 to chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (3,3- difluoropiperdin -4- base) tertiary fourth of carbamic acid is added in the suspension in ethyl alcohol (1mL) at 100mg, 0.442mmol) Solution of the ester (110mg, 0.464mmol) in ethyl alcohol (1mL).Then the reaction mixture is stirred 1 hour at -20 DEG C, this When LCMS indicate that the reaction is made slow progress.At -20 DEG C, triethylamine (0.062mL, 0.442mmol) is added into the reaction mixture In.The reaction mixture is warmed to 0 DEG C and is stirred 3 hours in the temperature.Then thio second is added into the reaction mixture Sour potassium (76mg, 0.664mmol) and Et3N (0.154mL, 1.106mmol).Then the heterogeneous reaction mixture is warmed to 20 DEG C and the temperature stir simultaneously with LCMS monitor process.After 20 DEG C are stirred overnight, first is added into the reaction mixture Sulfonic acid 2- amino -2- oxo -1- phenylethylester (101mg, 0.442mmol).The reaction is continued to stir at 20 DEG C.Stirring After 3.5 hours, additional ethyl alcohol (2mL) is added and the temperature is risen to 40 DEG C.By the heterogeneous reaction mixture 40 DEG C after Continuous stirring is for the weekend.The reaction mixture is cooled to room temperature.The solid is filtered and uses ethyl alcohol and water washing.Then by solid It dries in a vacuum drying oven, obtains (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- second Yl pyridines -2- base) -3,3- difluoropiperdin -4- base) t-butyl carbamate (140mg), be white solid, be used for Reaction afterwards is without being further purified.It takes 26mg aliquot and purifies (Gilson, 30mm x 50mm with reversed-phase HPLC Gemini column, NH4OH modifying agent), obtain (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano - 4- ethylpyridine -2- base) -3,3- difluoropiperdin -4- base) t-butyl carbamate (13mg) is white solid.LCMS m/z =579.3 [M+Na]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.97 (s, 1H), 7.50-7.56 (m, 2H), 7.27-7.43 (m, 5H), 5.55 (d, J=6.34Hz, 1H), 4.65-4.77 (m, 1H), 4.36-4.48 (m, 1H), 4.19 (br.s., 1H), 3.67-3.83 (m, 1H), 3.41-3.54 (m, 1H), 2.78 (q, J=7.60Hz, 2H), 1.89-2.00 (m, 1H), 1.71- 1.85 (m, 1H), 1.42 (s, 9H), 1.21 (t, J=7.60Hz, 3H).
Embodiment 384
4- ethyl -2- (4- methyl-1,4- Diazesuberane -1- base) -6- ((4- (4- methylpiperazine-1-yl) benzyl) Sulfenyl) pyridine -3,5- dimethoxy nitrile
At 20 DEG C, to (4- (4- methylpiperazine-1-yl) phenyl) methanol (103mg, 0.499mmol), DIEA Methane sulfonyl chloride is added at methylene chloride (2.5mL) in (0.131mL, 0.749mmol) and DMAP (6.10mg, 0.050mmol) (0.058mL, 0.749mmol).The reaction mixture is monitored into process with LCMS simultaneously in mutually synthermal stirring.It is stirred at 20 DEG C After 24 hours, which is concentrated and resulting materials normal-phase chromatography is purified into (Biotage Isolera, 10g SNAP ULTRA column, DCM/MeOH), obtain the brown solid of 123mg.At 0 DEG C, by a part of material (27mg) in N, N- bis- Solution in methylformamide (0.5mL) adds to 4- ethyl -2- sulfydryl -6- (4- methyl-1,4- Diazesuberane -1- base) pyrrole Pyridine -3,5- dimethoxy nitrile (synthesis, 46mg, 0.122mmol are described in embodiment 69, step 1) and Et3N (0.017mL, 0.122mmol) in the suspension in N,N-dimethylformamide (0.5mL).Then the reaction mixture is stirred at 0 DEG C Night.After 0 DEG C is stirred overnight, which is warmed to room temperature.The reaction mixture is filtered.By the filtrate reverse phase HPLC purifies (Gilson, 30mm x 50mm Gemini column, NH4OH modifying agent), then use reversed-phase HPLC repurity (Gilson, 30mm x 50mm Gemini column, NH4OH modifying agent), obtain 4- ethyl -2- (4- methyl-1,4- diaza cycloheptyl Alkane -1- base) -6- ((4- (4- methylpiperazine-1-yl) benzyl) sulfenyl) pyridine -3,5- dimethoxy nitrile (6mg) is yellow oil LCMS M/z=490.4 [M+H]+。1H NMR (400MHz, methanol-d4) δ ppm 7.26-7.30 (m, J=8.62Hz, 2H), 6.92- 6.97 (m, 2H), 4.44 (s, 2H), 3.95-4.03 (m, 4H), 3.18-3.24 (m, 4H), 2.91 (q, J=7.60Hz, 2H), 2.76-2.80 (m, 2H), 2.62-2.67 (m, 6H), 2.38 (s, 3H), 2.37 (s, 3H), 2.04-2.11 (m, 2H), 1.31 (t, J=7.60Hz, 3H).
Embodiment 385
4- ethyl -2- (4- methyl-1,4- Diazesuberane -1- base) -6- ((4- (((2- oxo-pyrrolidine -3- base) Amino) methyl) benzyl) sulfenyl) pyridine -3,5- dimethoxy nitrile
At 0 DEG C, to 2- ((4- (amino methyl) benzyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- diaza cycloheptyl Alkane -1- base) pyridine -3,5- dimethoxy nitrile dihydrochloride (synthesis, 53mg, 0.107mmol are described in embodiment 71) and Et3N 3- bromine pyrrolidin-2-one is added in (0.045mL, 0.322mmol) in the suspension in n,N-Dimethylformamide (0.5mL) The solution of (17mg, 0.104mmol) in n,N-Dimethylformamide (0.3mL).Then the reaction mixture is stirred at 0 DEG C Overnight.The temperature is risen to 20 DEG C and is stirred for the reaction mixture 24 hours mutually synthermal.By the reaction mixture mistake It filters and purifies (Gilson, 30mm Gemini column, NH with reversed-phase HPLC4OH modifying agent), obtain 4- ethyl -2- (4- methyl-1, 4- Diazesuberane -1- base) -6- ((4- (((2- oxo-pyrrolidine -3- base) amino) methyl) benzyl) sulfenyl) pyridine -3,5- Dimethoxy nitrile (6mg) is faint yellow oil.LCMS m/z=504.3 [M+H]+。1H NMR (400MHz, methanol-d4)δppm 7.34-7.42 (m, 4H), 4.51 (s, 2H), 3.93-4.01 (m, 4H), 3.80-3.90 (m, 2H), 3.38-3.43 (m, 1H), 3.37 (s, 2H), 3.25-3.31 (m, 1H), 2.92 (q, J=7.60Hz, 2H), 2.73-2.80 (m, 2H), 2.59-2.65 (m, 2H), 2.36 (s, 3H), 2.05 (td, J=5.92,11.22Hz, 2H), 1.92 (qd, J=9.17,12.55Hz, 1H), 1.32 (t, J=7.60Hz, 3H).
Embodiment 386:
2- ((3,5- dicyano -4- cyclopropyl -6- ((2- hydroxyethyl) (methyl) amino) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides
The chloro- 4- cyclopropyl -6- of step 1:2- ((2- hydroxyethyl) (methyl) amino) pyridine -3,5- dimethoxy nitrile
At 0 DEG C, (conjunction is described in embodiment 4, step 2 to chloro- 4- cyclopropyl pyridine -3, the 5- dimethoxy nitrile of 2,6- bis- It is molten in methylene chloride (10mL) at 0.5g, 2.100mmol) and 2- (methylamino) ethyl alcohol (0.166g, 2.205mmol) Triethylamine (0.585mL, 4.20mmol) is added in liquid.The mixture is stirred at room temperature 0.5 hour.By gained mixture vacuum Concentration.By residue silica gel chromatography (100g silica gel；Eluted with 3%MeOH/DCM), obtain the chloro- 4- cyclopropyl-of 2- 6- ((2- hydroxyethyl) (methyl) amino) pyridine -3,5- dimethoxy nitrile (0.5g), is yellow solid.LCMS m/z=276.9 [M+H]+。
Step 2:2- ((3,5- dicyano -4- cyclopropyl -6- ((2- hydroxyethyl) (methyl) amino) pyridine -2- base) sulphur Base) -2- phenyl-acetamides
To the chloro- 4- cyclopropyl -6- of 2- ((2- hydroxyethyl) (methyl) amino) pyridine -3,5- dimethoxy nitrile (0.5g) in N, Thioacetic acid potassium (0.310g, 2.71mmol) is added in solution in dinethylformamide (15mL).Then by the mixture It is stirred at room temperature 2 hours, then uses K2CO3(0.499g, 3.61mmol) processing.After being stirred at room temperature 0.5 hour, methylsulphur is added Sour 2- amino -2- oxo -1- phenylethylester (synthesis, 0.621g, 2.71mmol are described in embodiment 3, step 5) simultaneously will The mixture is stirred at room temperature overnight.Gained mixture is concentrated in vacuo.Remaining residue preparative-HPLC is purified, Obtain 2- ((3,5- dicyano -4- cyclopropyl -6- ((2- hydroxyethyl) (methyl) amino) pyridine -2- base) sulfenyl) -2- phenyl Acetamide (210mg), is pale solid.LCMS m/z=407.8 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.87 (s, 1H), 7.50 (d, J=7.3Hz, 2H), 7.42-7.30 (m, 4H), 5.52 (s, 1H), 4.80 (s, 1H), 3.93- 3.79 (m, 2H), 3.65 (s, 2H), 3.37 (s, 3H), 2.14-2.07 (m, 1H), 1.16-1.10 (m, 2H), 0.97-0.90 (m, 2H)。
Embodiment 387
2- ((3,5- dicyano -4- cyclopropyl -6- (3- hydroxy azetidine -1- base) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides
The chloro- 4- cyclopropyl -6- of step 1:2- (3- hydroxy azetidine -1- base) pyridine -3,5- dimethoxy nitrile
By chloro- 4- cyclopropyl pyridine -3, the 5- dimethoxy nitrile (1g, 4.20mmol) of 2,6- bis-, aza-cyclobutane -3-alcohol (0.307g, 4.20mmol) and triethylamine (0.425g, 4.20mmol) add in methylene chloride (50mL).By the mixture 25 DEG C stirring 3 hours.The solvent is removed and remaining residue is allocated between water (100mL) and DCM (100mL).It should Organic phase dries and concentrates.By the crude residue silica gel chromatography, 2- chloro- 4- cyclopropyl -6- (3- hydroxyl azepine is obtained Cyclobutane -1- base) pyridine -3,5- dimethoxy nitrile (700mg) is white solid.LCMS:m/z=275.0 [M+H]+。
Step 2:2- ((3,5- dicyano -4- cyclopropyl -6- (3- hydroxy azetidine -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides
To the chloro- 4- cyclopropyl -6- of 2- (3- hydroxy azetidine -1- base) pyridine -3,5- dimethoxy nitrile (700mg, Thioacetic acid potassium (582mg, 5.10mmol) 2.55mmol) is added in the solution in n,N-Dimethylformamide (50mL).It will The mixture stirs 2 hours at 25 DEG C, and methanesulfonic acid 2- amino -2- oxo -1- phenylethylester is then added (in embodiment 3, step Synthesis, 1168mg, 5.10mmol are described in rapid 5).The mixture is stirred 15 hours at 25 DEG C.The solvent is removed and incited somebody to action Remaining residue is allocated between water (100mL) and DCM (100mL).Insoluble solids are collected by filtration, the thick production is obtained Object.Crude material preparative-HPLC is purified, 2- ((3,5- dicyano -4- cyclopropyl -6- (3- hydroxyl azacyclo-s are obtained Butane -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides (210mg).LCMS m/z=405.8 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 7.87 (s, 1H), 7.51 (d, J=7.2Hz, 2H), 7.38-7.29 (m, 4H), 5.90 (d, J= 5.8Hz, 1H), 5.54 (s, 1H), 4.62-4.48 (m, 3H), 4.25-4.05 (m, 2H), 2.12-1.99 (m, 1H), 1.21- 1.03 (m, 2H), 0.99-0.87 (m, 2H).
Embodiment 388
1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) pyrrole Cough up alkane -3- formamide
Step 1:1- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) pyrrolidines -3- formamide
To chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (such as embodiment 3, the synthesis of step 2,1.6g, Triethylamine (0.716g, 7.08mmol) and pyrrolidines -3- first 7.08mmol) are added in the solution in methylene chloride (100mL) Amide (0.808g, 7.08mmol).The reaction mixture is stirred 15 hours at 25 DEG C.The solvent is removed and will be remaining residual Excess is allocated between water (50mL) and DCM (50mL).By organic phase Na2SO4It dries and concentrates.By the residue silica gel Chromatogram purification (uses 2:1 ethyl acetate: petroleum ether elution), obtains 1- (chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-) pyrrole Alkane -3- formamide (500mg) is coughed up, is Light brown solid.LCMS m/z=304.0 [M+H]+。
Step 2:1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) pyrrolidines -3- formamide
To 1- (chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-) pyrrolidines -3- formamide (500mg, Thioacetic acid potassium (188mg, 1.646mmol) 1.646mmol) is added in the solution in n,N-Dimethylformamide (40mL). The mixture is stirred 2 hours at 25 DEG C, be then added methanesulfonic acid 2- amino -2- oxo -1- phenylethylester (in embodiment 3, Synthesis, 377mg, 1.646mmol are described in step 5).The mixture is stirred 15 hours at 25 DEG C.The solvent is removed simultaneously Remaining residue is allocated between water (50mL) and DCM (50mL).Insoluble solids are collected by filtration, are slightly produced Object.By the crude material with preparative-HPLC purify, obtain 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3, 5- dicyano -4- ethylpyridine -2- base) pyrrolidines -3- formamide (400mg) is white solid.LCMS m/z=434.8 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.91 (d, J=6.5Hz, 1H), 7.61-7.48 (m, 3H), 7.41- (7.26 m, 4H), 7.07 (s, 1H), 5.61 (s, 0.5H), 5.59 (s, 0.5H), 3.95 (m, 4H), 3.05 (m, 1H), 2.75 (q, J=7.3Hz, 2H), 2.18 (m, 1H), 2.00 (m, 1H), 1.20 (t, 3H).
Embodiment 390:
2- (((1H- benzo [d] imidazoles -5- base) methyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- diaza cycloheptyl Alkane -1- base) pyridine -3,5- dimethoxy nitrile
Step 1:5- methyl-1 H- benzo [d] imidazoles -1- formic acid esters and 6- methyl-1 H- benzo [d] imidazoles -1- formic acid uncle Butyl ester
To 5- methyl-1 H- benzo [d] imidazoles (2.0g, 15.13mmol), triethylamine (5.27mL, 37.8mmol) two Di-tert-butyl dicarbonate (5.27mL, 22.70mmol) is added in solution in chloromethanes (30mL).By the reaction mixture in room Temperature is stirred overnight and dilutes acquired solution water (30mL), is extracted with ethyl acetate (3x 20mL).Organic layer is merged, is used Aqueous sodium carbonate and salt water washing, dry, filter and are concentrated in vacuo, and obtain 5- methyl-1 H- benzo [d] imidazoles -1- formic acid uncle The mixture (3.12g) of butyl ester and 6- methyl-1 H- benzo [d] imidazoles -1- t-butyl formate, is yellow oil.LCMS m/z= 177.1 [M+H- isobutenes]+。
Step 2:5- (bromomethyl) -1H- benzo [d] imidazoles -1- t-butyl formate and 6- (bromomethyl) -1H- benzo [d] Imidazoles -1- t-butyl formate
To 5- methyl-1 H- benzo [d] imidazoles -1- t-butyl formate and 6- methyl-1 H- benzene stirred under nitrogen at room temperature And the mixture (1.0g, 4.31mmol) and NBS (0.766g, 4.31mmol) of [d] imidazoles -1- t-butyl formate are in CCl4 AIBN (0.071g, 0.431mmol) is added in solution in (30mL).The reaction mixture is refluxed overnight.The reaction is mixed It closes object to be cooled to room temperature, is washed and be concentrated with water (3x 50mL), obtain 5- (bromomethyl) -1H- benzo [d] imidazoles -1- formic acid uncle The mixture (0.7g) of butyl ester and 6- (bromomethyl) -1H- benzo [d] imidazoles -1- t-butyl formate, is yellow oil.LCMS m/ Z=211.0 [M+H-boc]+。
Step 3:5- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) methyl) -1H- benzo [d] imidazoles -1- t-butyl formate and 6- (((3,5- dicyano -4- ethyl -6- (4- methyl - 1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) methyl) -1H- benzo [d] imidazoles -1- t-butyl formate
To 4- ethyl -2- sulfydryl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -3,5- dimethoxy nitrile (in reality Apply in 69 step 1 of example and describe synthesis, 581mg, 1.93mmol) and triethylamine (488mg, 4.82mmol) in DMF (20mL) Solution in 5- (bromomethyl) -1H- benzo [d] imidazoles -1- t-butyl formate and 6- (bromomethyl) -1H- benzo [d] miaow is added The mixture (600mg, 1.93mmol) of azoles -1- t-butyl formate.The reaction mixture is stirred at room temperature 2 hours.This is mixed Object is closed to pour into 20mL water.Acquired solution is extracted with ethyl acetate (3x 20mL).Merge organic layer, with salt water and water washing, Then it dries and concentrates.By the residue with silica gel column purification (hexane solution of 0-50% ethyl acetate), 5- (((3,5- is obtained Dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) methyl) -1H- benzo [d] Imidazoles -1- t-butyl formate and 6- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyrrole Pyridine -2- base) sulfenyl) methyl) and -1H- benzo [d] imidazoles -1- t-butyl formate mixture (410mg, 0.77mmol), for Huang Color solid.LCMS m/z=532.1 [M+H]+。
Step 4:2- (((1H- benzo [d] imidazoles -5- base) methyl) sulfenyl) -4- ethyl -6- (4- methyl-1,4- phenodiazine Trioxepane -1- base) pyridine -3,5- dimethoxy nitrile
To 5- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) methyl) -1H- benzo [d] imidazoles -1- t-butyl formate and 6- (((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) methyl) -1H- benzo [d] imidazoles -1- t-butyl formate (430mg, Trifluoroacetic acid (5.0mL) 0.81mmol) is added in the mixture in DCM (5.0mL), then by the reaction mixture in room temperature It is stirred overnight.By the residue diluted with water, Na is then used2CO3It is adjusted to pH 13.By acquired solution ethyl acetate (3x 15mL) extract.Organic layer is merged, with aqueous sodium carbonate and salt water washing, drying is simultaneously concentrated in vacuo.By the residue silicon Rubber column gel column purifies (hexane solution of 50% ethyl acetate), obtains 2- (((1H- benzo [d] imidazoles -5- base) methyl) sulfenyl) -4- Ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -3,5- dimethoxy nitrile (310mg, 0.71mmol), is yellow Oil.LCMS m/z=432.1 [M+H]+。1H NMR (400MHz, MeOD) δ ppm 8.18 (s, 1H), 7.67 (s, 1H), 7.59 (d, J=8.3Hz, 1H), 7.34 (d, J=8.3Hz, 1H), 4.65 (s, 2H), 3.97 (d, J=4.8Hz, 4H), 2.95-2.86 (m, 2H), 2.71-2.63 (m, 2H), 2.62-2.56 (m, 2H), 2.28 (s, 3H), 2.09-1.99 (m, 2H), 1.32 (t, J= 6.1Hz, 3H).
Embodiment 391
2- ((6- ((3- aminopropyl) (methyl) amino) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- Phenyl-acetamides, hydrochloride
Step 1:(3- ((the chloro- 3,5- dicyano -4- cyclopropyl pyridine -2- base of 6-) (methyl) amino) propyl) amino first Tert-butyl acrylate
At 0 DEG C, to chloro- 4- cyclopropyl pyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (in 4 step 2 of embodiment describe synthesis, Triethylamine (0.984mL, 7.06mmol) 1g) is added in the solution in methylene chloride (15mL), (3- (methyl ammonia is then added Base) propyl) t-butyl carbamate (0.996g, 5.29mmol).By the reaction mixture in mutually synthermal stirring 2 hours.It will The reaction mixture is diluted with methylene chloride (25mL) and is washed with water (100mL).By organic layer Na2SO4It dries, filters simultaneously It is concentrated under reduced pressure, obtains (3- ((chloro- 3, the 5- dicyano -4- cyclopropyl pyridine -2- base of 6-) (methyl) amino) propyl) carbamic acid The tert-butyl ester (800mg), is pale solid.LCMS m/z=390.5 [M+H]+。
Step 2:(3- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyrrole Pyridine -2- base) (methyl) amino) propyl) t-butyl carbamate
In room temperature, to (3- ((chloro- 3, the 5- dicyano -4- cyclopropyl pyridine -2- base of 6-) (methyl) amino) propyl) amino T-butyl formate (800mg) be added in the solution in n,N-Dimethylformamide (10mL) thioacetic acid potassium (447mg, 3.91mmol) and by the mixture stir 2 hours.Potassium carbonate (541mg, 3.91mmol) and first are added into the reaction mixture Sulfonic acid 2- amino -2- oxo -1- phenylethylester (describing synthesis, 992mg, 2.94mmol in 3 step 5 of embodiment) simultaneously will The mixture stirs 4 hours.Water (80mL) is added in the reaction and extracts the mixture ethyl acetate (2x 100mL). Combined organic layer is dried, filtered and is concentrated with anhydrous sodium sulfate.By crude material silica gel chromatography (100-200 Mesh, the petroleum ether solution of 70% ethyl acetate), obtain (3- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- Dicyano -4- cyclopropyl pyridine -2- base) (methyl) amino) propyl) t-butyl carbamate (550mg) is brown solid. LCMS m/z=521.4 [M+H]+。
Step 3:2- ((6- ((3- aminopropyl) (methyl) amino) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulphur Base) -2- phenyl-acetamides, hydrochloride
At 20 DEG C, to (3- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl Pyridine -2- base) (methyl) amino) propyl) and t-butyl carbamate (350mg) in the solution in 1,4- dioxanes (3mL) plus Enter HCl (Isosorbide-5-Nitrae-dioxane of 4M, 3.5mL, 14.00mmol).The reaction mixture is stirred at room temperature 4 hours.By second Ether (20mL) adds in the reaction mixture and obtains solid.The solid by filtration is collected, 2- ((6- ((3- amino is obtained Propyl) (methyl) amino) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- phenyl-acetamides, hydrochloride (250mg) is pale solid.LCMS m/z=421.2 [M+H]+。1H NMR (400MHz, DMSO-d6)δppm 8.04 (s, 1H), 7.95 (br s, 3H), 7.56-7.51 (m, 2H), 7.43-7.32 (m, 4H), 5.52 (s, 1H), 3.88-3.71 (m, 2H), 3.32 (s, 3H), 2.88-2.76 (m, 2H), 2.11 (tt, J=8.77,5.70Hz, 1H), 1.94 (quin, J= 7.45Hz, 2H), 1.18-1.11 (m, 2H) 0.99-0.93 (m, 2H).
Embodiment 392
2- ((3,5- dicyano -4- cyclopropyl -6- ((2- (3- hydroxy azetidine -1- base) -2- oxoethyl) (first Base) amino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides
Step 1:2- ((the chloro- 3,5- dicyano -4- cyclopropyl pyridine -2- base of 6-) (methyl) amino) tert-butyl acetate
At 0 DEG C, to chloro- 4- cyclopropyl pyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (in 4 step 2 of embodiment describe synthesis, Triethylamine (2.53mL, 17.77mmol) 4.5g) is added in the agitating solution in methylene chloride (45mL), 2- (first is then added Base amino) tert-butyl acetate (2.58g, 17.77mmol).By the reaction mixture in mutually synthermal stirring 2 hours.By the reaction Mixture is diluted with methylene chloride (200mL).Organic layer saturated sodium chloride solution (100mL), water (100mL) are washed, used Na2SO4It dries, filters and is concentrated under reduced pressure, obtain 5.8g crude product.Crude compound petroleum ether and a small amount of ether are ground Mill, is precipitated.The solid by filtration is collected, with excessive petroleum ether and is dried in vacuo, obtain 2- ((6- chloro- 3, 5- dicyano -4- cyclopropyl pyridine -2- base) (methyl) amino) tert-butyl acetate (5g) is pale solid.LCMS m/z =345.0 [M-H]-.
Step 2:2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyrrole Pyridine -2- base) (methyl) amino) tert-butyl acetate
In room temperature, to 2- ((chloro- 3, the 5- dicyano -4- cyclopropyl pyridine -2- base of 6-) (methyl) amino) tert-butyl acetate (5g) thioacetic acid potassium (2.470g, 21.19mmol) is added in the solution in n,N-Dimethylformamide (40mL) and should Mixture was in mutually synthermal stirring 2 hours.Then potassium carbonate (2.99g, 21.19mmol) and methanesulfonic acid 2- ammonia is added in room temperature Base -2- oxo -1- phenylethylester (describing synthesis, 4.32g in 3 step 5 of embodiment) simultaneously stirs the mixture in room temperature It mixes 2 hours.By the reaction mixture down to ice cold water (100mL), precipitating is resulted in.The solid by filtration is collected, is used Water (60mL) is washed and is dried in vacuo.By crude material silica gel chromatography (100-200 mesh, with the petroleum of 70%EtOAc Ethereal solution elution), obtain 2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyrrole Pyridine -2- base) (methyl) amino) tert-butyl acetate (3.2g) is pale solid.LCMS m/z=478.1 [M+H]+。
Step 3:2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyrrole Pyridine -2- base) (methyl) amino) acetic acid
At 0 DEG C, to 2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyrrole Pyridine -2- base) (methyl) amino) trifluoroacetic acid is added in the solution in methylene chloride (20mL) in tert-butyl acetate (2g) (0.5ml, 6.49mmol) and the reaction is stirred at room temperature 2 hours.The reaction mixture is concentrated under reduced pressure, it is thick to obtain this Product.Raw product is dissolved in methylene chloride (30mL) and is washed with saturated sodium bicarbonate aqueous solution (2x 20mL).By organic layer It is dried, filtered with anhydrous sodium sulfate and is concentrated in vacuo to dry, obtain 2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulphur Base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) (methyl) amino) acetic acid (1.6g) is brown solid.LCMS m/z =422.1 [M+H]+。
Step 4:2- ((3,5- dicyano -4- cyclopropyl -6- ((2- (3- hydroxy azetidine -1- base) -2- oxo second Base) (methyl) amino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides
In room temperature, to 2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl Pyridine -2- base) (methyl) amino) diisopropyl is added in the solution in N,N-dimethylformamide (5mL) in acetic acid (500mg) Ethamine (0.829mL, 4.75mmol) and HATU (677mg, 1.779mmol).After 15 minutes, by aza-cyclobutane -3-alcohol hydrochloric acid Salt (130mg, 1.186mmol) is added in room temperature and stirs the mixture 16 hours.Water (10mL) is added to the reaction to mix It is extracted in object and by the mixture with ethyl acetate (10mL).Organic layer is dried, filtered and is concentrated under reduced pressure with anhydrous sodium sulfate. Crude material preparative-HPLC is purified, 2- ((3,5- dicyano -4- cyclopropyl -6- ((2- (3- hydroxyl azacyclo-s are obtained Butane -1- base) -2- oxoethyl) (methyl) amino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides (165mg) are greyish white Color solid.LCMS m/z=477.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.83 (br d, J=9.65Hz, 1H), 7.54-7.44 (m, 2H), 7.42-7.26 (m, 4H), 5.75 (d, J=5.48Hz, 1H), 5.49 (d, J=9.21Hz, 1H), 4.68-4.24 (m, 4H), 4.16-4.06 (m, 1H), 3.97-3.87 (m, 1H) 3.66 (dt, J=10.14,4.91Hz, 1H), 3.29 (s, 3H), 2.16-2.07 (m, 1H), 1.16-1.09 (m, 2H), 0.99-0.90 (m, 2H).
Embodiment 393
2- ((6- (4- ((2- amino -2- oxoethyl) amino) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine - 2- yl) sulfenyl) -2- phenyl-acetamides
At 0 DEG C, to 2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides, stirring of the hydrochloride (describing synthesis, 500mg in 286 step 2 of embodiment) in methylene chloride (20mL) Triethylamine (0.273mL, 1.962mmol) is added in solution, 2- acetbromamide (135mg, 0.981mmol) then is added.It should Reaction is stirred at room temperature 14 hours.The reaction is quenched with water (40mL), separating layer and by water layer with methylene chloride (2x 50mL) Extraction.By combined organic layer anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure.The crude material is pure with preparative-HPLC Change, obtains 2- ((6- (4- ((2- amino -2- oxoethyl) amino) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides (200mg) are pale solid.LCMS m/z=478.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.89 (s, 1H), 7.55-7.48 (m, 2H), 7.42-7.25 (m, 5H), 7.04 (br s, 1H), 5.53 (s, 1H), 4.38 (d, J=13.81Hz, 2H), 3.39-3.31 (m, 2H), 3.11 (s, 2H), 2.80-2.69 (m, 3H), 1.90 (d, J=12.50Hz, 2H), 1.41-1.28 (m, 2H), 1.20 (t, J=7.56Hz, 3H).1 proton does not measure.
Embodiment 396
2- ((6- ((2- amino -2- oxoethyl) (methyl) amino) -3,5- dicyano -4- cyclopropyl pyridine -2- base) Sulfenyl) -2- phenyl-acetamides
Step 1:2- ((the chloro- 3,5- dicyano -4- cyclopropyl pyridine -2- base of 6-) (methyl) amino) acetamide
To 2- (methylamino) acetamide, hydrochloride (20.41g, 164mmol) stirring in methylene chloride (1000mL) Addition triethylamine (54.6mL, 378mmol) in solution is mixed, chloro- 4- cyclopropyl pyridine -3, the 5- dimethoxy nitrile of 2,6- bis- is then added (describing synthesis, 30g, 126mmol in 4 step 2 of embodiment).The reaction mixture is stirred at room temperature 1 hour.Water is added (1000mL) and the mixture is extracted with DCM (2x 1000mL).By combined organic layer Na2SO4It dries, filters and depressurizes Concentration, obtains the thick material.The crude material is passed through into silica gel chromatography (60-120 mesh；10%MeOH/EtOAc is used as and washes De- agent), obtain 2- ((chloro- 3, the 5- dicyano -4- cyclopropyl pyridine -2- base of 6-) (methyl) amino) acetamide (32g).LCMS M/z=290.4 [M+H]+。
Step 2:2- ((6- ((2- amino -2- oxoethyl) (methyl) amino) -3,5- dicyano -4- cyclopropyl pyridine - 2- yl) sulfenyl) -2- phenyl-acetamides
At 0 DEG C, to 2- ((chloro- 3, the 5- dicyano -4- cyclopropyl pyridine -2- base of 6-) (methyl) amino) acetamide (32g, 110mmol) in the agitating solution in n,N-Dimethylformamide (800mL) be added thioacetic acid potassium (18.92g, 166mmol).The reaction mixture is stirred at room temperature 30 minutes, then in 0 DEG C of addition K2CO3(22.90g, 166mmol) and first Sulfonic acid 2- amino -2- oxo -1- phenyl chlorocarbonate (describing synthesis, 25.3g, 110mmol in 3 step 5 of embodiment).This is anti- Mixture is answered to be stirred at room temperature 16 hours.Ice water (800mL) is added and extracts the ethyl acetate solution of 5% methanol of the mixture Take (2x 1000mL).Combined organic layer is dried, filtered and is concentrated under reduced pressure with Na2SO4, the crude product is obtained.This is crude Material uses neutral alumina (10%MeOH/EtOAc as eluant, eluent), obtains residue by chromatogram purification.By the remnants Object is suspended in the diethyl ether solution (1000mL) of 10% ethyl alcohol, continues 6 hours, filtering, by collected solid with ether (500mL) Washing and drying.The solid is dissolved in ethyl alcohol (15L, 3 crowdes), filter and the filtrate decompression is concentrated, obtains material requested.It should Material is suspended in ethyl alcohol (500mL), continues 2 hours, and filtering washs collected solid with ethyl alcohol (300mL), dry, obtains To 2- ((6- ((2- amino -2- oxoethyl) (methyl) amino) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- Phenyl-acetamides (22g), are pale solid.LCMS m/z=421.0 [M+H]+。1H NMR (400MHz, DMSO-d6) δ Ppm 7.75 (s, 1H), 7.55 (br s, 1H), 7.48-7.51 (m, 2H), 7.24-7.41 (m, 5H), 5.57 (s, 1H), 4.49 (d, J=17.10Hz, 1H), 4.26 (d, J=17.10Hz, 1H), 3.31-3.40 (m, 3H), 2.11 (tt, J=8.74, 5.62Hz, 1H), 1.07-1.22 (m, 2H), 0.89-1.01 (m, 2H).
Embodiment 397
Carbamic acid 2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyrrole Pyridine -2- base) (methyl) amino) ethyl ester
The chloro- 4- cyclopropyl -6- of step 1:2- ((2- hydroxyethyl) (methyl) amino) pyridine -3,5- dimethoxy nitrile
It is molten to stirring of 2- (methylamino) ethyl alcohol (0.303g, 3.95mmol) in methylene chloride (10mL) at 0 DEG C In liquid be added triethylamine (0.842mL, 5.92mmol), be then added chloro- 4- cyclopropyl pyridine -3, the 5- dimethoxy nitrile of 2,6- bis- ( Synthesis, 1.0g are described in 4 step 2 of embodiment) and stir the reaction mixture 1 hour mutually synthermal.The reaction is mixed Object is closed to be diluted with methylene chloride (100mL) and washed with saturated sodium chloride solution (40mL) and water (50mL).Organic layer is used Na2SO4It dries, filters and is concentrated under reduced pressure.By the crude material petroleum ether and a small amount of triturated under ether, precipitated.This is sunk Shallow lake is collected by filtration, and with excessive petroleum ether and is dried in vacuo, and obtains the chloro- 4- cyclopropyl -6- of 2- ((2- hydroxyethyl) (methyl) amino) pyridine -3,5- dimethoxy nitrile (1.0g) is pale solid.LCMS m/z=277.1 [M+H]+。
Step 2: carbamic acid 2- ((the chloro- 3,5- dicyano -4- cyclopropyl pyridine -2- base of 6-) (methyl) amino) ethyl Ester
At 0 DEG C, to the chloro- 4- cyclopropyl -6- of 2- ((2- hydroxyethyl) (methyl) amino) pyridine -3,5- dimethoxy nitrile Zassol (1.343g, 13.01mmol) is added in the agitating solution in toluene (20mL) in (1.0g), and trifluoroacetic acid is then added (1.002mL, 13.01mmol).The reaction mixture is stirred at room temperature 16 hours.By the reaction mixture ethyl acetate (100mL) is diluted and is washed with saturated sodium bicarbonate aqueous solution (50mL) and water (100mL).By organic layer Na2SO4It is dry, mistake It filters and is concentrated under reduced pressure.By the crude material petroleum ether and a small amount of triturated under ether, sediment is obtained.The precipitating is passed through into filtering It collects and is dried in vacuo, obtain carbamic acid 2- ((chloro- 3, the 5- dicyano -4- cyclopropyl pyridine -2- base of 6-) (methyl) amino) Ethyl ester (0.8g), is pale solid.LCMS m/z=320.1 [M+H]+。
Step 3: carbamic acid 2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ring PropyIpyridine -2- base) (methyl) amino) ethyl ester
In room temperature, to carbamic acid 2- ((chloro- 3, the 5- dicyano -4- cyclopropyl pyridine -2- base of 6-) (methyl) amino) second Base ester (0.800g) be added in the agitating solution in n,N-Dimethylformamide (10mL) thioacetic acid potassium (0.381g, 3.27mmol) and by the reaction it is stirred at room temperature 2 hours.Into the reaction mixture be added potassium carbonate (0.460g, 3.27mmol) and methanesulfonic acid 2- amino -2- oxo -1- phenylethylester (describe synthesis in 3 step 5 of embodiment, 0.665g) and by the reaction it is stirred at room temperature 1 hour.The reaction mixture down to ice cold water (50mL) and is used into ethyl acetate (200mL) extraction.Organic layer saturated brine solution (100mL), water (300mL) are washed, dried, filtered with anhydrous sodium sulfate And it is concentrated under reduced pressure.The crude material is washed and is dried in vacuo with acetonitrile (20mL), carbamic acid 2- ((6- ((2- amino-is obtained 2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine -2- base) (methyl) amino) ethyl ester (370mg) is pale solid.LCMS m/z=451.1 [M+H]+。1H NMR (400MHz, DMSO-d6)δppm 7.81 (s, 1H), 7.53-7.47 (m, 2H), 7.42-7.29 (m, 4H), 6.57 (br s, 2H), 5.54 (s, 1H), 4.21-4.12 (m, 2H), 4.08-3.91 (m, 2H), 3.37 (s, 3H), 2.16-2.06 (m, 1H), 1.17-1.10 (m, 2H), 0.99-0.92 (m, 2H)。
Embodiment 398
(2R) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- second Yl pyridines -2- base) piperidin-4-yl) -3- hydroxypropanamide
Step 1:((2R) -1- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- Ethylpyridine -2- base) piperidin-4-yl) amino) -3- hydroxyl -1- oxo propyl- 2- yl) t-butyl carbamate
In room temperature, to (R) -2- ((tertbutyloxycarbonyl) amino) -3- hydracrylic acid (362mg, 1.729mmol) in N, N- Diisopropylethylamine (0.770mL, 4.32mmol) is added in agitating solution in dimethylformamide (15mL).The reaction is mixed Object is closed in mutually synthermal stirring 5 minutes, is then added at one time HATU (671mg, 1.729mmol) and 2- ((6- (4- amino piperazine Pyridine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides, hydrochloride is (in 286 step of embodiment Synthesis, 400mg, 0.864mmol are described in 2) and stir gained reaction mixture 2 hours.By the reaction mixture with cold Water (100mL) dilutes and stirs 15 minutes to form precipitating.The precipitating is collected by filtered on buchner funnel, with excessive washing It washs and is dried in vacuo.The thick material solid is ground with ether (30mL), obtains ((2R) -1- ((1- (6- ((2- amino -2- oxygen Generation -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl) amino) -3- hydroxyl -1- oxo Propyl- 2- yl) t-butyl carbamate (500mg) is pale solid.LCMS m/z=608.2 [M+H]+。
Step 2:(2R) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyan Base -4- ethylpyridine -2- base) piperidin-4-yl) -3- hydroxypropanamide
At 5 DEG C, to ((2R) -1- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano - 4- ethylpyridine -2- base) piperidin-4-yl) amino) -3- hydroxyl -1- oxo propyl- 2- yl) t-butyl carbamate (500mg) exists Hydrochloric acid (Isosorbide-5-Nitrae-dioxane of 4M, 1.748mL, 6.99mmol) is added in agitating solution in Isosorbide-5-Nitrae-dioxanes (10mL). Gained reaction mixture is stirred at room temperature 5 hours.The reaction mixture ether (50mL) is diluted and is stirred at room temperature 10 Minute, it is precipitated.The solid is collected by filtered on buchner funnel, is washed and is dried in vacuo with excess diethyl ether.This is crude Material is purified with preparative-HPLC, obtains (2R) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulphur Base) -3,5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl) -3- hydroxypropanamide (140mg) is pale solid. LCMS m/z=508.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.89 (s, 1H), 7.80 (d, J=7.67Hz, 1H), 7.54-7.46 (m, 2H), 7.42-7.25 (m, 4H), 5.53 (s, 1H), 4.68 (t, J=5.48Hz, 1H), 4.44 (br T, J=12.28Hz, 2H), 3.91 (br s, 1H), 3.51 (dt, J=10.03,4.96Hz, 1H), 3.43-3.33 (m, 3H), 3.18 (t, J=5.59Hz, 1H), 2.76 (q, J=7.60Hz, 2H), 1.88-1.80 (m, 4H), 1.57-1.45 (m, 2H), 1.21 (t, J=7.56Hz, 3H).
Embodiment 399:
(2S) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- second Yl pyridines -2- base) piperidin-4-yl) -3- hydroxypropanamide
Step 1:((2S) -1- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- Ethylpyridine -2- base) piperidin-4-yl) amino) -3- hydroxyl -1- oxo propyl- 2- yl) t-butyl carbamate
In room temperature, to (S) -2- ((tertbutyloxycarbonyl) amino) -3- hydracrylic acid (91mg, 0.432mmol) in N, N- bis- Diisopropylethylamine (0.770mL, 4.32mmol) is added in agitating solution in methylformamide (15mL).The reaction is mixed Then object is added at one time HATU (671mg, 1.729mmol) and 2- ((6- (4- amino piperidine-in mutually synthermal stirring 5 minutes 1- yl) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides, hydrochloride is (in 286 step 2 of embodiment Describe synthesis, 400mg) and stir gained reaction mixture 2 hours.The reaction mixture is diluted with cold water (100mL) And stir 15 minutes, obtain solid.The solid is collected by filtered on buchner funnel, with excessive water washing and is dried in vacuo.It will The solid is ground with ether (30mL), obtain ((2S) -1- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3, 5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl) amino) -3- hydroxyl -1- oxo propyl- 2- yl) t-butyl carbamate (520mg) is pale solid.LCMS m/z=609.0 [M+H]+。
Step 2:(2S) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyan Base -4- ethylpyridine -2- base) piperidin-4-yl) -3- hydroxypropanamide
At 5 DEG C, to ((2S) -1- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano - 4- ethylpyridine -2- base) piperidin-4-yl) amino) -3- hydroxyl -1- oxo propyl- 2- yl) t-butyl carbamate (500mg) exists Hydrochloric acid (Isosorbide-5-Nitrae-dioxane of 4M, 1.770mL, 7.08mmol) is added in agitating solution in Isosorbide-5-Nitrae-dioxanes (15mL). Gained reaction mixture is stirred at room temperature 5 hours.The reaction mixture ether (50mL) is diluted and is stirred at room temperature 10 Minute, it is precipitated.The solid of precipitation is collected by filtered on buchner funnel, is washed and is dried in vacuo with excessive ether.It will The crude material is purified with preparative-HPLC, obtains (2S) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenyl second Base) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl) -3- hydroxypropanamide (260mg) is canescence Solid.LCMS m/z=508.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.87 (s, 1H), 7.78 (d, J= 7.89Hz, 1H), 7.52-7.46 (m, 2H), 7.39-7.27 (m, 4H), 5.51 (s, 1H), 4.66 (t, J=5.48Hz, 1H), 4.42 (br t, J=11.84Hz, 2H), 3.84-3.96 (m, 1H), 3.49 (dt, J=10.25,5.07Hz, 1H), 3.40- 3.30 (m, 3H), 3.19-3.13 (m, 1H), 2.74 (q, J=7.67Hz, 2H), 1.91-1.75 (m, 4H), 1.56-1.41 (m, 2H), 1.19 (t, J=7.67Hz, 3H).
Embodiment 400:
2- (4- (2- amino -2- oxoethyl) phenyl) -2- (3,5- dicyano -4- ethyl -6- (4- methyl-1,4- bis- Azepan -1- base) pyridine -2- base sulfenyl) acetamide
Step 1:2,2'- (1,4- phenylene) diacetonitrile
By Isosorbide-5-Nitrae-two (bromomethyl) benzene (8.0g, 30.3mmol) and potassium cyanide (4.80g, 73.6mmol) in ethyl alcohol Mixture in (80.0mL) and water (40mL) stirs 3 hours at 50-60 DEG C.Water (300mL) is added in the mixture.By institute Mixture is obtained to be extracted with DCM (3x 200mL).Combined organic layer is washed with water (200mL) three times and with salt water (200mL) Washing, is then concentrated, obtains 2,2'- (Isosorbide-5-Nitrae-phenylene) diacetonitrile (4.3g, 91% yield), be white solid.1H NMR (400MHz, CDCl3) δ 7.39 (s, 4H), 3.79 (s, 4H).
The bromo- 2- of step 2:2- (4- (cyano methyl) phenyl) acetonitrile
By 2,2'- (Isosorbide-5-Nitrae-phenylene) diacetonitrile (2.3g, 14.73mmol), 1- bromine pyrrolidines -2,5- diketone (2.6g, 14.73mmol), benzoyl hydroperoxide acid anhydride (0.36g, 1.47mmol) is in CCl4Mixture in (30mL) is small in 75-80 DEG C of stirring 4 When.By 2,2'- (Isosorbide-5-Nitrae-phenylene) diacetonitrile (2.0g, 12.81mmol), 1- bromine pyrrolidines -2,5- diketone (2.279g, 12.81mmol), benzoyl hydroperoxide acid anhydride (0.310g, 1.281mmol) is in CCl4The second reaction mixture in (30mL) is in 75- 80 DEG C are stirred 4 hours.The mixture is merged, is then concentrated.Residue purification by flash chromatography (is used into petroleum ether: acetic acid Ethyl ester=20:1-1:1 elution), obtain the bromo- 2- of 2- (4- (cyano methyl) phenyl) acetonitrile (2.6g, 11.1mmol).1H NMR (400MHz, CDCl3) δ ppm 7.32 (d, J=8.2Hz, 2H), 7.17 (d, J=8.1Hz, 2H), 5.23 (s, 1H), 3.51 (s, 2H)。
Step 3:2- (4- (2- amino -2- oxoethyl) phenyl) -2- acetbromamide
By the bromo- 2- of 2- (4- (cyano methyl) phenyl) acetonitrile (1.5g, 6.38mmol), acetamide (3.8g, 63.80mmol) and the mixture of palladium chloride (II) (0.11g, 0.64mmol) in tetrahydrofuran (15mL) and water (5.00mL) It deaerates, is then stirred 3 hours at 20-30 DEG C under vacuum.The mixture is concentrated.DCM (30mL) and MeOH (10mL) is added And the mixture is stirred 1 hour.The mixture is filtered, is then dried in vacuo, 2- (4- (2- amino -2- oxo second is obtained Base) phenyl) -2- acetbromamide (670mg, 39%).LCMS m/z=270.9 [M+H]+。
Step 4:2- (4- (2- amino -2- oxoethyl) phenyl) -2- (3,5- dicyano -4- ethyl -6- (4- methyl - 1,4- Diazesuberane -1- base) pyridine -2- base sulfenyl) acetamide
By 4- ethyl -2- sulfydryl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -3,5- dimethoxy nitrile (in reality Apply in 69 step 1 of example and describe synthesis, 267mg, 0.89mmol), 2- (4- (2- amino -2- oxoethyl) phenyl) -2- bromine second The mixing of amide (200mg, 0.74mmol) and triethylamine (112mg, 1.11mmol) in n,N-Dimethylformamide (10mL) Object stirs 2 hours at 20-30 DEG C.The mixture is filtered and is washed with water, it is then that the filter cake and MeOH and water stirring 1 is small When, then filter.The filter cake is stirred 3 hours with DMSO (30mL), water (120mL) then is added dropwise.After stirring 16 hours, by this Mixture is filtered and is washed with water, and is then dried, and 2- (4- (2- amino -2- oxoethyl) phenyl) -2- ((3,5- dicyan are obtained Base -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) (116mg, 32% produces acetamide Rate).LCMS m/z=492.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.90 (s, 1H), 7.48 (s, 1H), 7.42 (d, J=8.1Hz, 2H), 7.33 (s, 1H), 7.26 (d, J=8.0Hz, 2H), 6.88 (s, 1H), 5.50 (s, 1H), 4.01-3.92 (m, 2H), 3.91-3.85 (m, 2H), 3.37 (s, 2H), 2.77 (q, J=7.6Hz, 2H), 2.72-2.63 (m, 2H), 2.55 (s, 2H), 2.28 (s, 3H), 2.00-1.90 (m, 2H), 1.21 (t, J=7.6Hz, 3H).
Embodiment 401:
2- (4- (2- amino -2- oxoethyl) phenyl) -2- (3,5- dicyano -6- (dimethylamino) -4- ethyl pyrrole Pyridine -2- base sulfenyl) acetamide
By 2- chloro- 6- (dimethylamino) -4- ethylpyridine -3,5- dimethoxy nitrile (208mg, 0.89mmol), thioacetic acid Potassium (describing synthesis, 101mg, 0.89mmol in 3 step 3 of embodiment), triethylamine (187mg, 1.84mmol) are in N, N- bis- Mixture in methylformamide (10mL) stirs 1 hour at 20-30 DEG C.2- (4- (2- amino -2- oxoethyl) benzene is added Base) -2- acetbromamide (describing synthesis, 200mg, 0.74mmol in 400 step 3 of embodiment), then the mixture is existed 20-30 DEG C is stirred 16 hours.Water (30mL) is added and stirs the mixture, then stirs the mixture 1 hour, filtering is simultaneously It is washed with water.The filter cake is stirred 1 hour with ethyl acetate (30mL), is then filtered, it is dry, obtain 2- (4- (2- amino -2- Oxoethyl) phenyl) -2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) acetamide (150mg, 48% yield).LCMS m/z=423.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm7.89 (s, 1H), 7.48 (s, 1H), 7.44 (d, J=8.1Hz, 2H), 7.31 (s, 1H), 7.25 (d, J=8.0Hz, 2H), 6.89 (s, 1H), 5.57 (s, 1H), 3.36 (s, 2H), 3.35 (s, 6H), 2.75 (q, J=7.5Hz, 2H), 1.20 (t, J=7.6Hz, 3H).
Embodiment 402:
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (4- (N- methyl ammonia sulphur Acyl group) phenyl) acetamide
2- (dimethylamino) -4- ethyl -6- mercaptopyridine -3,5- dimethoxy nitrile (is described in 92 step 3 of embodiment Synthesis, 200mg, 0.86mmol), methanesulfonic acid 2- amino -1- (4- (N- Methylsulfamoyl) phenyl) -2- oxoethyl ester (describing synthesis, 319mg, 0.99mmol in 378 step 4 of embodiment) and triethylamine (0.360mL, 2.58mmol) are in DMF Mixture in (10mL) stirs 16 hours at 55 DEG C.Then it is concentrated and residue DCM is extracted and is washed with water. Organic layer in vacuo is concentrated into dry doubling the residue is purified with column chromatography, obtains 2- ((3,5- dicyano -6- (dimethylaminos Base) -4- ethylpyridine -2- base) sulfenyl) -2- (4- (N- Methylsulfamoyl) phenyl) acetamide (36mg, 9% yield).LCMS M/z=459.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.04 (s, 1H), 7.77 (m, 4H), 7.53-7.38 (m, 2H), 5.72 (s, 1H), 3.31 (s, 6H), 2.75 (d, J=7.6Hz, 2H), 2.43 (t, J=6.3Hz, 3H), 1.20 (t, J= 7.5Hz, 3H).
Embodiment 403:
4- ethyl -2- (4- methyl-1,4- Diazesuberane -1- base) -6- (4- (sulfonyloxy methyl ylmethyl) dibenzylsulfide Base) pyridine -3,5- dimethoxy nitrile
Step 1:4- (methylsulfanylmethyl) methyl benzoate
Disposably, the sodium methyl mercaptide (0.734g, 9.95mmol) of 0 DEG C of Xiang stirring is in the solution in methanol (30mL) Methyl 4- (bromomethyl) benzoic ether (1.9g, 8.29mmol) is added.The reaction mixture is stirred at room temperature 16 hours.It should Reaction mixture is diluted with water (250mL), is allocated between ethyl acetate (100mL) and water (250mL).By the organic phase water (10mL) washing, is dried and concentrated with sodium sulphate.Residue silica gel column purification (is eluted) with hexane/EtOAc, obtains 4- (methylsulfanylmethyl) methyl benzoate (1.5g, 92% yield).LCMS m/z=197.0 [M+H]+。
Step 2:4- (sulfonyloxy methyl ylmethyl) methyl benzoate
At 120 DEG C, by 4- ((methylsulfany) methyl) methyl benzoate (500mg, 2.55mmol) and H2O2(5mL, Stirring 2 hours in acetic acid (10mL) of mixture 16mmol).The reaction is concentrated in vacuo, water (10mL) then is added dropwise, obtains White solid.The solid is filtered and is dried in vacuo, obtain 4- ((methyl sulphonyl) methyl) methyl benzoate (500mg, 2.19mmol, 86% yield), it is white solid.LCMS m/z=228.9 [M+H]+。
Step 3:(4- (sulfonyloxy methyl ylmethyl) phenyl) methanol
To 4- ((methyl sulphonyl) methyl) methyl benzoate (400mg, 1.75mmol) stirred at 0 DEG C in tetrahydro furan It mutters and solid hydride aluminium (III) lithium (133mg, 3.50mmol) is added portionwise in the solution in (30mL).The reaction mixture is existed It is stirred at room temperature 2 hours.It is added dropwise water (0.15mL), then 10%NaOH (0.45mL).The mixture is filtered and the filtrate is dense Contracting, obtains (4- (sulfonyloxy methyl ylmethyl) phenyl) methanol.LCMS m/z=183 [M+H-18]+。
Step 4:1- (chloromethyl) -4- (sulfonyloxy methyl ylmethyl) benzene
Exist to (4- ((methyl sulphonyl) methyl) phenyl) methanol (269mg, 1.34mmol) stirred in 0 DEG C of air Thionyl chloride (0.392mL, 5.37mmol) is added dropwise in solution in methylene chloride (30mL).The reaction mixture is stirred in room temperature It mixes 1 hour, is then concentrated, obtain 1- (chloromethyl) -4- (sulfonyloxy methyl ylmethyl) benzene (294mg, 100% yield).LCMS m/ Z=219 [M+H]+。
Step 5:4- ethyl -2- (4- methyl-1,4- Diazesuberane -1- base) -6- (4- (sulfonyloxy methyl ylmethyl) Benzyl sulfenyl) pyridine -3,5- dimethoxy nitrile
In room temperature, by 1- (chloromethyl) -4- ((methyl sulphonyl) methyl) benzene (400mg, 1.83mmol), triethylamine (0.765mL, 5.49mmol) and 4- ethyl -2- sulfydryl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -3,5- bis- The mixture of formonitrile HCN (describing in 69 step 1 of embodiment, 551mg, 1.83mmol) is in n,N-Dimethylformamide (30mL) Stirring 2 hours.The mixture is concentrated and the residue silica gel column purification (is used into CH2Cl2/ MeOH elution), obtain 4- second Base -2- (4- methyl-1,4- Diazesuberane -1- base) -6- (4- (sulfonyloxy methyl ylmethyl) benzyl sulfenyl) pyridine -3,5- two Formonitrile HCN (120mg, 0.24mmol, 13% yield).LCMS m/z=483.8 [M+H]+。1H NMR (400MHz, MeOD) δ ppm 7.45 (q, J=8.3Hz, 4H), 4.55 (s, 2H), 4.43 (s, 2H), 4.01-3.96 (m, 2H), 3.93 (t, J=6.1Hz, 2H), 2.99-2.91 (m, 2H), 2.90 (s, 3H), 2.84-2.79 (m, 2H), 2.72-2.66 (m, 2H), 2.41 (s, 3H), 2.08-2.00 (m, 2H), 1.31 (t, 3H).
Embodiment 404
2- ((3,5- dicyano -6- (dimethylamino-d6) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides
The chloro- 6- of step 1:2- (dimethylamino-d6) -4- ethylpyridine -3,5- dimethoxy nitrile
At 0 DEG C, to chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (synthesis is described in embodiment 3, step 2, 2.5g, 11.06mmol), dimethylamine-d6, hydrochloride (1.017g, 11.61mmol) is added dropwise in the solution in ethyl alcohol (30mL) Et3N (3.39mL, 24.33mmol).Gained mixture is stirred 60 minutes at 0 DEG C, is then stirred at room temperature 2 hours.It will 150mL water adds in the reaction and stirs gained mixture 30 minutes.Gained is precipitated and is filtered, it is 2 hours dry in pump, so Drying is for the weekend in vacuum drying oven afterwards, obtains the chloro- 6- of 2- (dimethylamino-d6) -4- ethylpyridine -3,5- dimethoxy nitrile (950mg, 3.95mmol, 36% yield), is pale solid.LCMS m/z=241.0 [M+H]+。
Step 2:2- ((3,5- dicyano -6- (dimethylamino-d6) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide
Be added into 20-mL bottle thioacetic acid S- (2- amino -2- oxo -1- phenylethyl) ester (in embodiment 62, Synthesis, 191mg, 0.914mmol are described in step 5), ethyl alcohol (10mL) and the mixture is heated to flowing back.Then in batches NaBH is added4(47.1mg, 1.246mmol).The reaction is stirred at reflux 45 minutes, then cool to room temperature and solid 2- is added Chloro- 6- (dimethylamino-d6) -4- ethylpyridine -3,5- dimethoxy nitrile (200mg, 0.831mmol).The reaction mixture is existed It is stirred at room temperature 1 hour.Gained mixture is filtered, it is with ethanol washing and the residue is 1 hour dry in pump, then true Drying is for the weekend in empty baking oven, obtains 2- ((3,5- dicyano -6- (dimethylamino-d6) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides (270mg, 0.727mmol, 87% yield) are white solid.LCMS m/z=372.2 [M+H ]+。1H NMR(DMSO-d6) δ ppm 7.94 (s, 1H), 7.48-7.57 (m, 2H), 7.25-7.43 (m, 4H), 5.60 (s, 1H), 2.75 (q, J=7.6Hz, 2H), 1.20 (t, J=7.5Hz, 3H).
Embodiment 405:
(R) -2- ((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides
The chloro- 4- ethyl -6- of step 1:2- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -3,5- dimethoxy nitrile:
It (is described in embodiment 3, step 2 in 0 DEG C of chloro- 4- ethylpyridine -3,5- dimethoxy nitrile of 2,6- bis- stirred Synthesis, 300mg, 1.327mmol) in the solution in methylene chloride (40mL) be added dropwise 4- (pyrrolidin-1-yl) piperidines (205mg, 1.327mmol) and the solution of triethylamine (0.222mL, 1.592mmol) in DCM (20mL).By the reaction mixture in room temperature Stirring 2 hours.The reaction mixture is allocated between methylene chloride (100mL) and water (100mL).The organic phase is saturated Salt water (25mL) washing with sodium sulphate drying and is evaporated in vacuo, obtains the chloro- 4- ethyl -6- of thick material 2- (4- (pyrrolidines -1- Base) piperidin-1-yl) pyridine -3,5- dimethoxy nitrile (508mg, 100% yield, 90% purity) is yellow solid.LCMS m/z =344.2 [M+H]+。
Step 2:(R) -2- ((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides:
At 20 DEG C, by the chloro- 4- ethyl -6- of 2- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -3,5- dimethoxy nitrile The mixture of (508mg, 1.330mmol, 90% purity) and thioacetic acid potassium (182mg, 1.596mmol) is in N, N- dimethyl methyl Stirring 30 minutes in amide (20mL).Then triethylamine (0.222mL, 1.596mmol) and 4- toluenesulfonic acid are sequentially added (S) -2- amino -2- oxo -1- phenylethylester (describing synthesis, 487mg, 1.596mmol in 418 step 3 of embodiment). The mixture is stirred overnight at 20 DEG C.The reaction mixture is allocated between ethyl acetate (100mL) and water (100mL). Organic phase water (50mL), saturated brine (50mL) are washed, with sodium sulphate drying and is evaporated in vacuo, obtains crude product.It will The crude product adds to silica gel (12g) column and is eluted with DCM:MeOH=10:1, obtains (R) -2- ((3,5- dicyano -4- ethyls - 6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- phenyl-acetamides (80mg, 0.163mmol, 12% Yield), it is white solid.LCMS m/z=475.3 [M+H]+。1H NMR (400MHz, MeOD) δ 7.53-7.52 (m, 2H), 7.41-7.35 (m, 3H), 5.50 (s, 1H), 4.78-4.68 (m, 2H), 3.52-3.12 (m, 2H), 2.88 (q, J=7.6Hz, 2H), 2.69-2.66 (m, 4H), 2.41-2.39 (m, 1H), 2.12-2.08 (m, 2H), 1.85-1.83 (m, 4H), 1.58-1.53 (m, 2H), 1.29 (t, J=7.6Hz, 3H).
Embodiment 406:
(R) -2- ((3,5- dicyano -6- (4- (dimethylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides
At 20 DEG C, by the chloro- 6- of 2- (4- (dimethylamino) piperidin-1-yl) -4- ethylpyridine -3,5- dimethoxy nitrile (in reality Example 207 is applied, synthesis, 300mg, 0.850mmol, 90% purity are described in step 1) and thioacetic acid potassium (116mg, Stirring 30 minutes in N,N-dimethylformamide (20mL) of mixture 1.019mmol).Then triethylamine is sequentially added (0.142mL, 1.019mmol) and 4- toluenesulfonic acid (S) -2- amino -2- oxo -1- phenylethylester is (in 418 step of embodiment Synthesis, 311mg, 1.019mmol are described in rapid 3).The mixture is stirred overnight at 20 DEG C.The reaction mixture is distributed Between ethyl acetate (100mL) and water (100mL).Organic phase water (50mL), saturated brine (50mL) are washed, sulphur is used Sour sodium is dry and is evaporated in vacuo, and obtains the crude product.Crude product is added into silica gel (12g) column and is eluted with DCM:MeOH=5:1, Obtain (R) -2- ((3,5- dicyano -6- (4- (dimethylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide (94mg, 0.210mmol, 25% yield), is white solid.LCMS m/z=449.3 [M+H]+。1H NMR (400MHz, DMSO) δ 7.93 (s, 1H), 7.54-7.52 (m, 2H), 7.39-7.35 (m, 4H), 5.54 (s, 1H), 4.58-4.55 (m, 2H), 3.18 (t, J=11.9Hz, 2H), 2.83-2.64 (m, 2H), 2.42-2.35 (m, 1H), 2.19 (s, 6H), 1.88- 1.85 (m, 2H), 1.41-1.36 (m, 2H), 1.20 (t, J=7.2Hz, 3H).
Embodiment 407:
2- (3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base sulfenyl) -2- (3- (2- (dimethylamino Base) ethyoxyl) phenyl) acetamide
Step 1:3- (2- (dimethylamino) ethyoxyl) benzonitrile:
In room temperature, sodium methoxide is added in the solution in toluene (200mL) to 3- hydroxy benzonitrile (10g, 84mmol) The solution of (4.54g, 84mmol) in methanol (40.0mL).The methanol is distilled at 100 DEG C, obtains white solid.At 0 DEG C, To the chloro- N of 2-, unsaturated carbonate is added in the solution in toluene (200mL) in N- dimethylethylamine hydrochloride (12.09g, 84mmol) Sodium solution (50mL) simultaneously stirs 4 hours.The organic phase is separated and above-mentioned white solid is added into the chloro- N of 2-, N- dimethyl amine Organic layer.Then the reaction mixture is stirred 12 hours at 65 DEG C.The reaction mixture is filtered, is evaporated in vacuo, obtains Crude product is white solid.Raw product is added into silicagel column (150g) and uses CH2Cl2: MeOH (gradient: 30:1-10:1), 3- (2- (dimethylamino) ethyoxyl) benzonitrile (1.5g, 7.88mmol, 9% yield) is obtained, is yellow oil.LCMS m/z= 191.0[M+H]+。
Step 2:3- (2- (dimethylamino) ethyoxyl) benzaldehyde
By 3- (2- (dimethylamino) ethyoxyl) benzonitrile (1.4g, 7.36mmol) and nickel (0.086g, 1.472mmol) Suspension in formic acid (10mL) 125 DEG C stirred under nitrogen 5 hours.The organic phase is filtered and is evaporated in vacuo, is obtained thick Product processed is yellow solid.
The crude product is added into silicagel column (100g) and uses CH2Cl2: MeOH (gradient: 100:1-10:1) elution obtains 3- (2- (dimethylamino) ethyoxyl) benzaldehyde (1g), is yellow oil.LCMS m/z=194.2 [M+H]+。
Step 3:2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (3- (2- (dimethylamino) ethyoxyl) phenyl) acetamide:
By 3- (2- (dimethylamino) ethyoxyl) benzaldehyde (900mg, 4.66mmol) and potassium phthalimide The solution of (108mg, 0.582mmol) in trimethylsilyl cyanide (10mL, 75.0mmol) is stirred at room temperature overnight.This is organic It is mutually evaporated in vacuo, obtains thick material, be yellow solid.By the solution of the yellow solid (500mg) hydrochloride (10mL, Stirring 12 hours in 120mmol).The reaction mixture is evaporated in vacuo, raw product is obtained, is brown solid.It is solid to this Methane sulfonyl chloride (196mg, 1.71mmol) and triethylamine (0.949mL, 6.81mmol) are added in body at methylene chloride (20mL) In solution and the mixture is stirred at room temperature overnight.The organic phase is evaporated in vacuo, methanesulfonic acid 2- amino -1- (3- is obtained (2- (dimethylamino) ethyoxyl) phenyl) -2- oxoethyl ester (700mg) is brown solid.By the chloro- 6- (dimethyl of 2- Amino) -4- ethylpyridine -3,5- dimethoxy nitrile (describing synthesis, 519mg, 2.21mmol in 3 step 3 of embodiment), triethylamine The solution of (672mg, 6.64mmol) and thioacetic acid potassium (278mg, 2.434mmol) in n,N-Dimethylformamide (30mL) It is stirred at room temperature 2 hours.Then methanesulfonic acid 2- amino -1- (3- (2- (dimethylamino) ethyoxyl) phenyl) -2- oxo is added Ethyl ester (700mg) simultaneously stirs the mixture 12 hours at 60 DEG C.The organic phase is evaporated in vacuo, brown liquid is obtained, it will It adds to silicagel column (50g) and uses CH2Cl2: MeOH (gradient: 30:1-10:1) elution obtains 2- ((3,5- dicyano -6- (two Methylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (3- (2- (dimethylamino) ethyoxyl) phenyl) acetamide (20.5mg, 0.045mmol) is white solid.LCMS m/z=452.9 [M+H]+。1H NMR (400MHz, CDCl3)δ 7.34-7.29 (m, 1H), 7.13-7.05 (m, 2H), 6.91 (d, J=7.9Hz, 1H), 6.76 (br.s, 1H), 5.61 (s, 1H), 5.43 (s, 1H), 4.34 (br.s, 2H), 3.43 (s, 6H), 3.20 (m, 2H), 2.94 (q, J=7.7Hz, 2H), 2.70 (s, 6H), 1.34 (t, J=7.5Hz, 3H).
Embodiment 408:
2- ((3,5- dicyano -4- ethyl -6- (4- (neopentyl amino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- (4- fluorophenyl) acetamide
Step 1:2- ((3,5- dicyano -4- ethyl -6- (4- oxo-piperidine -1- base) pyridine -2- base) sulfenyl) -2- (4- Fluorophenyl) acetamide
At -20 DEG C, to chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (in 3 step 2 of embodiment describe synthesis, 360mg, 1.592mmol) and suspension of the piperidin-4-one hydrochloride monohydrate (245mg, 1.592mmol) in ethyl alcohol (5mL) The solution of triethylamine (0.444mL, 3.18mmol) in ethyl alcohol (5mL) is added in liquid.By the reaction mixture mutually synthermal Stir 2h.Then thioacetic acid potassium (218mg, 1.911mmol) and Et are added into the reaction mixture3N (0.555mL, 3.98mmol).The reaction mixture is warmed to 40 DEG C and stirs 3h in the temperature.Methanesulfonic acid is added into the reaction mixture 2- amino -1- (4- fluorophenyl) -2- oxoethyl ester (describe synthesis in 207 step 3 of embodiment, 591mg, 2.389mmol) and by the reaction at 40 DEG C it is stirred overnight.The non-homogeneous mixture is cooled to room temperature and is filtered.It will be collected Solid ethyl alcohol, water, ethyl alcohol and Et2O washing, then dries, obtains 2- ((3,5- dicyano -4- ethyl -6- (4- oxo piperazines Pyridine -1- base) pyridine -2- base) sulfenyl) -2- (4- fluorophenyl) acetamide (425mg) is white solid.LCMS m/z= 438.0[M+H]+。
Step 2:2- ((3,5- dicyano -4- ethyl -6- (4- (neopentyl amino) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- (4- fluorophenyl) acetamide
In room temperature, to 2- ((3,5- dicyano -4- ethyl -6- (4- oxo-piperidine -1- base) pyridine -2- base) sulfenyl) -2- (4- fluorophenyl) acetamide (75mg, 0.171mmol) is in methylene chloride (DCM) (0.5mL) and tetrahydrofuran (THF) (0.5mL) In suspension in 2,2- dimethyl propylene -1- amine (0.022mL, 0.189mmol) is added.The reaction mixture is stirred at room temperature Then sodium triacetoxy borohydride (109mg, 0.514mmol) is added in 1h.After being stirred at room temperature 3 hours, which is mixed Object concentration.Resulting materials are dissolved in DMSO and methanol and purified with reversed-phase HPLC (Gilson, 30mmx 50mm Gemini column, NH4OH modifying agent), obtain 2- ((3,5- dicyano -4- ethyl -6- (4- (neopentyl amino) piperidin-1-yl) pyridine -2- base) Sulfenyl) -2- (4- fluorophenyl) acetamide (35mg) is pale solid.LCMS m/z=509.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 7.96 (s, 1H), 7.56 (dd, J=5.4,8.7Hz, 2H), 7.38 (s, 1H), 7.22 (t, J= 8.7Hz, 2H), 5.56 (s, 1H), 4.44-4.32 (m, 2H), 3.33-3.28 (m, 2H), 2.75 (q, J=7.5Hz, 2H), 2.68 (br.s., 1H), 2.31 (s, 2H), 1.92 (d, J=11.2Hz, 2H), 1.41-1.26 (m, 2H), 1.24 (s, 1H), 1.20 (t, J=7.6Hz, 3H), 0.87 (s, 9H).
Embodiment 409:
2- ((3,5- dicyano -4- ethyl -6- (the fluoro- 4- of 3- (neopentyl amino) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides
Step 1:2- ((3,5- dicyano -4- ethyl -6- (3- fluorin-4-oxygen is for piperidin-1-yl) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides
At -20 DEG C, (conjunction is described in embodiment 3, step 2 to chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- 3- fluorine resources -4- ketone is added in the suspension in ethyl alcohol (5mL) at 500mg, 2.212mmol), hydrochloride (357mg, 2.322mmol) and triethylamine (0.617mL, 4.42mmol) is in the solution in ethyl alcohol (5mL).By the reaction mixture -20 DEG C stirring 2h.Then thioacetic acid potassium (379mg, 3.32mmol) and Et are added into the reaction mixture3N (0.771mL, 5.53mmol).The reaction mixture is warmed to 40 DEG C and stirs 3h in the temperature.Methanesulfonic acid is added into the reaction mixture 2- amino -2- oxo -1- phenylethylester (synthesis, 1.02g, 4.45mmol are described in embodiment 3, step 5).At 40 DEG C After being stirred overnight, which is cooled to room temperature and is concentrated.Resulting materials are allocated between ethyl acetate and water.It will Organic layer separation simultaneously extracts aqueous layer with ethyl acetate (2x).Combined organic layer is washed with saturated brine, is dried and concentrated, Obtain crude product.By the crude product purified by silica gel chromatogram purification (ISCO120g SNAP ULTRA column, Hex/ EtOAc 50-100%), obtain 2- ((3,5- dicyano -4- ethyl -6- (3- fluorin-4-oxygen is for piperidin-1-yl) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides (497mg) are light tan solid.LCMS m/z=438.1 [M+H]+。
Step 2:2- ((3,5- dicyano -4- ethyl -6- (the fluoro- 4- of 3- (neopentyl amino) piperidin-1-yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides
In room temperature, to 2- ((3,5- dicyano -4- ethyl -6- (3- fluorin-4-oxygen is for piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides (50mg, 0.114mmol) are in methylene chloride (DCM) (0.5mL) and tetrahydrofuran (THF) (0.5mL) Mixture in solution in 2,2- dimethyl propylene -1- amine (0.020mL, 0.171mmol) is added.By the reaction mixture in room Temperature stirring 1h, is added sodium triacetoxy borohydride (37mg, 0.175mmol) at this time.After 2h is stirred at room temperature, which is mixed Close object concentration.Resulting materials are dissolved in the mixture of DMSO and MeOH and purify (Gilson, 30mmx 50mm with reversed-phase HPLC Gemini column, NH4OH modifying agent), obtain 2- ((3,5- dicyano -4- ethyl -6- (the fluoro- 4- of 3- (neopentyl amino) piperidines -1- Base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides (20mg) are white solid.LCMS m/z=509.2 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 7.96 (s, 1H), 7.56-7.49 (m, 2H), 7.42-7.31 (m, 4H), 5.57-5.51 (m, 1H), 5.01-4.78 (m, 2H), 4.59-4.49 (m, 1H), 3.57-3.39 (m, 1H), 3.24-3.12 (m, 1H), 2.87-2.71 (m, 3H), 2.42-2.30 (m, 2H), 1.92-1.80 (m, 1H), 1.72-1.51 (m, 1H), 1.33 (q, J=8.3Hz, 1H), 1.21 (t, J=7.6Hz, 3H), 0.88 (s, 9H).
Embodiment 410:
2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- (4- (trifluoro Methyl) phenyl) acetamide
Step 1:(1- (6- ((2- amino -2- oxo -1- (4- (trifluoromethyl) phenyl) ethyl) sulfenyl) -3,5- dicyan Base -4- ethylpyridine -2- base) piperidin-4-yl) t-butyl carbamate
At -20 DEG C, (conjunction is described in embodiment 3, step 2 to chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- Be added in the suspension in ethyl alcohol (1mL) at 50mg, 0.221mmol) piperidin-4-yl t-butyl carbamate (46mg, 0.230mmol) and the solution of triethylamine (0.032mL, 0.232mmol) in ethyl alcohol (2mL).By the reaction mixture identical Temperature stirs 2h.Then thioacetic acid potassium (32mg, 0.280mmol) and Et are added into the reaction mixture3N (0.077mL, 0.553mmol).The reaction mixture is warmed to 20 DEG C and stirs 4h, then in 40 DEG C of heating 3h.Into the reaction mixture Methanesulfonic acid 2- amino -2- oxo -1- (4- (trifluoromethyl) phenyl) ethyl ester is added (to describe in embodiment 233, step 2 Synthesis, 99mg, 0.332mmol).The reaction is heated overnight at 40 DEG C.After the heterogeneous reaction mixture is cooled to room temperature, The solid by filtration that will be present is collected, and uses ethyl alcohol, water, ethyl alcohol, Et in succession2O washing, then dries, obtains (1- (6- ((2- Amino -2- oxo -1- (4- (trifluoromethyl) phenyl) ethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidines -4- Base) t-butyl carbamate (68mg) is white solid.LCMS m/z=589.2 [M+H]+.The filtrate is concentrated, will be remained Remaining residue reversed-phase HPLC purifies (Gilson, 30mm x 50mm Gemini column, NH4OH modifying agent), it obtains additional (1- (6- ((2- amino -2- oxo -1- (4- (trifluoromethyl) phenyl) ethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) piperidin-4-yl) t-butyl carbamate (48mg) is white solid.LCMS m/z=589.2 [M+H]+。
Step 2:2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- (4- (trifluoromethyl) phenyl) acetamide
In room temperature, by (1- (6- ((2- amino -2- oxo -1- (4- (trifluoromethyl) phenyl) ethyl) sulfenyl) -3,5- bis- Cyano -4- ethylpyridine -2- base) piperidin-4-yl) t-butyl carbamate (53mg, 0.090mmol) is suspended in 4M HCl In the solution of (1.000mL, 4.0mmol) in dioxanes.3h is stirred at room temperature in the reaction mixture, is then concentrated.By institute Material be dissolved in it is in the mixture of DMSO and MeOH and free-basing with isopropylamine.The mixture is purified with reversed-phase HPLC (Gilson, 30mmx 50mm Gemini column, NH4OH modifying agent), obtain 2- ((6- (4- amino piperidine -1- base) -3,5- dicyan Base -4- ethylpyridine -2- base) sulfenyl) -2- (4- (trifluoromethyl) phenyl) acetamide 11mg is pale solid.LCMS M/z=489.0 [M+H]+.In individual experiment, in room temperature, by (1- (6- ((2- amino -2- oxo -1- (4- (fluoroform Base) phenyl) ethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl) t-butyl carbamate (41mg, 4M HCl (1.000mL, 4.00mmol) 0.070mmol) is suspended in the solution in dioxanes.By the reaction mixture in room Temperature stirring 3h, is then concentrated.By resulting materials be dissolved in the mixture of DMSO and MeOH and with isopropylamine it is free-basing.This is dissociated The material of alkalization merge with the material (11mg) of above-mentioned purifying and combined mixture reversed-phase HPLC is purified (Gilson, 30mmx 50mm Gemini column, NH4OH modifying agent), obtain 2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- second Yl pyridines -2- base) sulfenyl) -2- (4- (trifluoromethyl) phenyl) acetamide (15mg) is faint yellow solid.LCMS m/z= 489.0[M+H]+。1H NMR (400MHz, DMSO-d6) δ 8.07 (s, 1H), 7.84-7.69 (m, 4H), 7.49 (s, 1H), 5.68 (s, 1H), 4.41-4.28 (m, 2H), 3.32-3.22 (m, 2H), 2.95-2.86 (m, 1H), 2.75 (q, J=7.6Hz, 2H), 1.95-1.66 (m, 4H), 1.35-1.17 (m, 5H).
Embodiment 411:
2- ((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides
Step 1:2- ((3,5- dicyano -4- ethyl -6- (4- oxo-piperidine -1- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide
At 0 DEG C, to chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (in 3 step 2 of embodiment describe synthesis, 0.653g, 2.89mmol) and piperidin-4-one, hydrochloride, monohydrate (0.444g, 2.89mmol) is in ethyl alcohol (20mL) Triethylamine (0.443mL, 3.18mmol) is added dropwise in slurries.5h is stirred into the reaction.Then to being added at one time sulphur in the reaction For potassium acetate (0.495g, 4.33mmol) and triethylamine (1.007mL, 7.22mmol).After being stirred overnight (~15h) at 20 DEG C, By methanesulfonic acid 2- amino -2- oxo -1- phenylethylester (describe synthesis in 3 step 5 of embodiment, 1.324g, It 5.78mmol) disposably adds in the reaction and by the reaction in 40 DEG C of stirring 5h.There is solid.The reaction is cooled to room Temperature.The mixture is diluted with water (~25mL) and is filtered by polyethylene sinter funnel (ChemGlass OP-6602).By institute The solid of collection is successively washed with water (2x20mL), ethyl alcohol (2x20mL) and ether (2x20mL), then in 60 DEG C of vacuum drying ovens In be thoroughly dried overnight, obtain 2- ((3,5- dicyano -4- ethyl -6- (4- oxo-piperidine -1- base) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides (0.66g, 55%), are pale solid.LCMS m/z=420.0 [M+H]+。
Step 2:2- ((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides
To 2- ((3,5- dicyano -4- ethyl -6- (4- oxo-piperidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl second Pyrrolidines is added in the suspension in tetrahydrofuran (1mL) and methylene chloride (1mL) in amide (0.049g, 0.117mmol) (0.014mL, 0.175mmol).After 15min is stirred at room temperature, addition sodium triacetoxy borohydride (0.037g, 0.175mmol).After 6h, which is homogenized.The purifying of the reaction solution uses reversed-phase HPLC (0.1%NH4OH modifying agent, C18 50x30mm Gemini column), obtain 2- ((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) Pyridine -2- base) sulfenyl) -2- phenyl-acetamides (33mg, 60%) are white solid.LCMS m/z=475.1 [M+H]+。1H NMR (400MHz, chloroform-d) δ ppm 7.51-7.32 (m, 5H), 6.63 (br.s., 1H), 5.84 (br.s, 1H), 5.35 (s, 1H), 4.63 (dd, J=3.4,13.6Hz, 2H), 3.36-3.16 (m, 2H), 2.92 (q, J=7.6Hz, 2H), 2.72 (br.s., 4H), 2.44 (br.s, 1H), 2.15-2.03 (m, 2H), 1.95-1.67 (m, 6H), 1.33 (t, J=7.7Hz, 3H).
Embodiment 412:
(R) -2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl Acetamide, hydrochloride
Step 1:(R)-(1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) t-butyl carbamate
At 20 DEG C, by (1- (6- chloro- 3,5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl) tertiary fourth of carbamic acid Ester (describing synthesis, 500mg, 1.154mmol in applying 81 step 1 of example) and thioacetic acid potassium (132mg, 1.154mmol) Mixture stirring 30 minutes in N,N-dimethylformamide (20mL).Then sequentially add triethylamine (0.193mL, 1.385mmol) (retouched in embodiment 418, step 3 with 4- toluenesulfonic acid (S) -2- amino -2- oxo -1- phenylethylester Synthesis, 352mg, 1.154mmol are stated).The mixture is stirred overnight at 20 DEG C.The reaction mixture is allocated in acetic acid second Between ester 100mL and water 100mL.Organic phase water 50mL, saturated brine 50mL are washed, steamed with sodium sulphate is dry with vacuum Hair, obtains crude product.The raw product is added into silica gel (12g) column and uses CH2Cl2/ MeOH (50/1) elution, obtains (R)-(1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidin-4-yl) amino T-butyl formate (240mg, 0.429mmol, 37% yield), is white solid.LCMS m/z=465.2 [M+H-t-Bu]+。
Step 2:(R) -2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides, hydrochloride
By (R)-(1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) piperidin-4-yl) suspension of the t-butyl carbamate (50mg, 0.096mmol) in HCl (4M is in dioxanes) (2mL) Liquid is stirred at room temperature 1 hour.The reaction is concentrated in the case where not heating, obtains raw product, is white solid.With system Standby type-HPLC purifies (10-95-A-CN (0.1%FA)-H2O (0.1%TFA)).Then (0 DEG C) is concentrated, with the dioxanes of HCl Then solution (2mL) processing, concentration are handled with the dioxane (2mL) of HCl, then concentration is lyophilized, obtains (R) -2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides, hydrochloride (12mg, 0.026mmol, 27% yield), is light gray solid.LCMS m/z=421.0 [M+H]+。1H NMR(DMSO-d6) δppm1H NMR (400MHz, DMSO) δ 8.24-7.94 (m, 3H), 7.53 (d, J=7.7Hz, 2H), 7.46-7.31 (m, 3H), 5.56 (s, 1H), 4.59 (d, J=13.8Hz, 2H), 3.51-3.47 (m, 1H), 3.45-3.40 (m, 2H), 3.33-3.20 (m, 2H), 2.78 (q, J=7.5Hz, 2H), 2.15-2.01 (m, 2H), 1.69-1.52 (m, 2H), 1.22 (t, J=7.6Hz, 3H).
Embodiment 413
2- ((6- ((2- amino -2- oxoethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides (single enantiomer)
By 2- ((6- ((2- amino -2- oxoethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) Sulfenyl) -2- phenyl-acetamides racemic mixture (3.00g) be dissolved in the part 200mg 360 volumes (72mL) boiling 1:1 Methanol: purify in ethyl alcohol and with chirality HPLC (Chiralpak AD-H, 5 microns (50mm x 250mm), 100mL/min.Stream Speed, 30:70 normal heptane: ethyl alcohol (constant gradient is not necessarily to modifying agent)).Each run 50mg racemic modification carries out 60 chiralitys in total Preparation.It is collected into the reaction mixture for the enantiomter 2 that total amount is about 15L.The solution is concentrated to substantially dry, obtains stock white Material.The white slurry is filtered to collect the product.Use ethanol rinse.The wet cake is dried under 45 DEG C of high vacuum to final perseverance Determine weight, obtains 2- ((6- ((2- amino -2- oxoethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) Sulfenyl) -2- phenyl-acetamides (1.247g) are white solid.LCMS m/z=409.1 [M+H]+.Optical activity: α D=- 318 ° (DMSO, 23 DEG C, C=0.20).1H NMR(DMSO-d6) δ 7.83 (s, 1H), 7.62 (s, 1H), 7.44-7.55 (m, 2H), 7.24-7.43 (m, 5H), 5.59 (s, 1H), 4.52 (d, J=17.2Hz, 1H), 4.29 (d, J=17.2Hz, 1H), 3.39 (s, 3H), 2.77 (q, J=7.5Hz, 2H), 1.20 (t, J=7.6Hz, 3H).
Embodiment 414:
2- { [3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base] sulfanyl } -2- phenyl-acetamides
(in 135 step 2 of embodiment conjunction is described to the chloro- 4- of 2,6- bis- (furans -2- base) pyridine -3,5- dimethoxy nitrile 1- methyl-1,4- diaza cycloheptyl are added dropwise in the solution in n,N-Dimethylformamide (3mL) at 300mg, 1.136mmol) Then TEA (115mg, 1.14mmol) is added dropwise in alkane (123mg, 1.079mmol).The reaction is stirred at room temperature 1 hour.By sulphur The mixture is added to for potassium acetate (130mg, 1.136mmol).The reaction is stirred at room temperature 30 minutes, then by N- (4- (chlorine Methyl) benzyl) acetamide (describing synthesis, 225mg, 1.136mmol in 336 step 3 of embodiment) and TEA (230mg, 2.28mmol) add to the solution.The mixture is stirred at room temperature overnight.The mixture is concentrated in vacuo.Raw product is led to It crosses silica gel chromatography (being eluted with MeOH-DCM 0-10%) and uses Et2O grinding, obtains N- (4- (((3,5- dicyano -4- (furans -2- base) -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) methyl) benzyl) acetamide (100mg, 0.199mmol, 18% yield), is brown solid.LCMS m/z=500.8 [M+H]+。1H NMR (400MHz, MeOD) δ 7.88 (d, J=1.5Hz, 1H), 7.43-7.37 (m, 3H), 7.28 (d, J=8.1Hz, 2H), 6.75 (dd, J=3.6, 1.8Hz, 1H), 4.53 (s, 2H), 4.36 (s, 2H), 4.02-3.91 (m, 4H), 2.83-2.76 (m, 2H), 2.67-2.61 (m, 2H), 2.37 (s, 3H), 2.11-2.04 (m, 2H), 2.00 (s, 3H).1 proton does not measure.
Embodiment 415:
Biphosphate (3S) -1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl Pyridine -2- base) pyrrolidin-3-yl ester
Step 1: phosphoric acid (3S) -1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- second Yl pyridines -2- base) pyrrolidin-3-yl ester di-t-butyl ester
In room temperature, to phosphoric acid (S)-(1- (chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-) pyrrolidin-3-yl) ester Two-the tert-butyl esters (describing synthesis, 10.0g, 21.33mmol in 418 step 2 of embodiment) are in n,N-Dimethylformamide (DMF) thioacetic acid potassium (3.65g, 32.0mmol) is added in the agitating solution in (200mL) and in 50 DEG C of stirring 16hr.It should Reaction mixture is cooled to room temperature, and K then is added in room temperature2CO3(4.42g, 32.0mmol) and methanesulfonic acid 2- amino -2- oxo - 1- phenylethylester (describes synthesis, 4.89g, 21.33mmol in 3 step 5 of embodiment).By gained reaction mixture in room Temperature stirring 18hr.The reaction mixture ice cold water (1000mL) is diluted and stirs 10min, is precipitated.By consolidating for precipitation Body filtering, it is dry, obtain thick material.The crude material neutral aluminum oxide column chromatography is purified into (eluant, eluent: 80%EtOAc Petroleum ether solution), obtain phosphoric acid (3S) -1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano - 4- ethylpyridine -2- base) pyrrolidin-3-yl ester di-t-butyl ester (4.5g, 34%) is Light brown solid.LCMS(m/z) =600.1 [M+H]+。
Step 4: dihydrogen phosphoric acid (3S) -1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano - 4- ethylpyridine -2- base) pyrrolidin-3-yl ester
In room temperature, to phosphoric acid (3S) -1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano - 4- ethylpyridine -2- base) stirring of the pyrrolidin-3-yl ester di-t-butyl ester (3.0g, 5.00mmol) in ethyl alcohol (40mL) be molten The diethyl ether solution of 2.0M hydrochloric acid (20mL, 40.0mmol) is added in liquid.Gained reaction mixture is stirred at room temperature 1 hour.It will The reaction mixture is concentrated under reduced pressure, and obtains crude material.Altogether by the crude material and EtOH (50mL) and ether (50mL) It distills (5 times) and with triturated under ether, is precipitated.The solid of precipitation is filtered, it is dry, obtain biphosphate (3S) -1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) pyrrolidin-3-yl ester (2.180g, 88%), is pale solid.LCMS (m/z): 487.8 [M+H]+。1H NMR (400MHz, DMSO-d6)δppm 11.30 (s, 1H), 7.90 (s, 1H), 7.52 (d, J=7.02Hz, 2H), 7.41-7.21 (m, 4H), 5.61 (s, 1H), 4.94 (s., 1H), 4.10-3.78 (m, 4H), 2.75 (q, J=7.5Hz, 2H), 2.29-2.08 (m, 2H), 1.20 (t, J=7.56Hz, 3H)。
Embodiment 416:
Biphosphate (3R) -1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl Pyridine -2- base) pyrrolidin-3-yl ester
By 2- ((3,5- dicyano -4- ethyl -6- ((R) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- Mixing of the phenyl-acetamides (describing synthesis, 0.5g, 1.227mmol in 168 step 2 of embodiment) in polyphosphoric acid (5mL) Object is stirred overnight at 50 DEG C.The mixture trash ice is handled and is stirred at room temperature overnight.By gained mixture preparative- HPLC purifies (0.1%TFA modifying agent), obtains biphosphate (3R) -1- (6- ((2- amino -2- oxo -1- phenylethyl) sulphur Base) -3,5- dicyano -4- ethylpyridine -2- base) pyrrolidin-3-yl ester (200mg, 33% yield) is white solid. LCMS m/z=487.7 [M+H]+。1H NMR (400MHz, DMSO) δ ppm11.98-10.32 (br s, 2H), 7.93 (s, 1H), 7.53 (d, J=7.2Hz, 2H), 7.42-7.26 (m, 4H), 5.61 (s, 1H), 4.95 (s, 1H), 4.09-3.81 (m, 4H), 2.76 (q, J=7.3Hz, 2H), 2.28-2.09 (m, 2H), 1.21 (t, J=7.5Hz, 3H).
Embodiment 417:
Biphosphate (S) -1- (6- (((S) -2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- Ethylpyridine -2- base) pyrrolidin-3-yl ester
Step 1:4- toluenesulfonic acid (R) -2- amino -2- oxo -1- phenylethylester
In room temperature, to (R) -2- hydroxyl -2- phenyl-acetamides (30g, 198mmol) in Isosorbide-5-Nitrae-dioxanes (300mL) DIPEA (104mL, 595mmol) and DMAP (2.425g, 19.85mmol) are added in agitating solution.The reaction mixture is cooling To 0 DEG C, Ts-Cl (56.8g, 298mmol) is then added portionwise into the reaction mixture and is stirred at room temperature 16 hours.It should Reaction mixture stirs 10min down to ice cold water (2000mL), and solid is precipitated.The solid of precipitation is filtered, it is dry, it obtains The crude compound.The crude material is ground with ether (2x 500mL), is filtered, it is dry, obtain 4- toluenesulfonic acid (R)- 2- amino -2- oxo -1- phenylethylester (35g, 56%), is pale solid.LCMS m/z=306.1 [M+H]+。
Step 2: phosphoric acid (S) -1- (6- (((S) -2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano - 4- ethylpyridine -2- base) pyrrolidin-3-yl ester di-t-butyl ester
In room temperature, to phosphoric acid (S)-(1- (chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-) pyrrolidin-3-yl) ester Two-the tert-butyl esters (describing synthesis, 40.0g, 85mmol in 418 step 2 of embodiment) are at n,N-Dimethylformamide (DMF) Thioacetic acid potassium (14.61g, 128mmol) is added in agitating solution in (400mL) and stirs 2 hours.In room temperature, by TEA (17.83mL, 128mmol) and 4- toluenesulfonic acid (R) -2- amino -2- oxo -1- phenylethylester (26.0g, 85mmol) add Into the reaction mixture and stir 18 hours.The reaction mixture is diluted with ice cold water (2000mL) and with EtOAc (3x 1500mL) extract.Combined organic layer is washed with ice cold water (3x 2000mL), saline solution (1000mL), use is anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure, obtain crude material.By the crude material ether (200mL) and pentane (500mL) grinding, is filtered, dry, obtains brown solid.The solid material is dissolved in EtOAc (1000mL) and is passed throughFiltering.The filtrate is concentrated under reduced pressure, phosphoric acid (S) -1- (6- (((S) -2- amino -2- oxo -1- phenyl is obtained Ethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) pyrrolidin-3-yl ester di-t-butyl ester (40.02g, It 66.3%), is Light brown solid.LCMS m/z=600.3 [M+H]+。
Step 3: biphosphate (S) -1- (6- (((S) -2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyan Base -4- ethylpyridine -2- base) pyrrolidin-3-yl ester
At 0 DEG C, to phosphoric acid (S) -1- (6- (((S) -2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyan Base -4- ethylpyridine -2- base) pyrrolidin-3-yl ester di-t-butyl ester (40.0g, 56.5mmol) is in ether (800mL) and second The diethyl ether solution of 2.0M hydrochloric acid (400mL, 800mmol) is added in agitating solution in alcohol (400mL).The reaction mixture is existed It is stirred at room temperature 2 hours.The reaction mixture is concentrated under reduced pressure, crude compound is obtained.By the crude material and EtOH (400mL) and ether (800mL) condistillation (3 times) is simultaneously thoroughly dried, and Light brown solid is obtained.By solid EtOH The grinding of the mixture of (400mL) and ether (800mL), is filtered, dry, obtains biphosphate (S) -1- (6- (((S) -2- amino - 2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) pyrrolidin-3-yl ester (19.0g, 69%), It is pale solid.LCMS m/z=488.0 [M+H]+.By biphosphate (S) -1- (6- (((S) -2- amino-of two batches 2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) pyrrolidin-3-yl ester (4.65g and 19.0g) merge and be dissolved in ethyl alcohol (4.0L) and evaporate the solution under reduced pressure, obtains pale solid.By solid EtOH It grinds, filters with the mixture (300:600mL) of ether, it is dry, obtain pale solid.The solid is thoroughly ground, is obtained Biphosphate (S) -1- (6- (((S) -2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) pyrrolidin-3-yl ester (21.1g) is pale solid.LCMS m/z=488.0 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 7.89 (s, 1H), 7.56-7.50 (m, 2H), 7.41-7.30 (m, 3H), 7.25 (s, 1H), 5.61 (s, 1H), 4.97-4.90 (m, 1H), 4.10-3.92 (m, 3H), 3.90-3.80 (m, 1H), 2.75 (q, J=7.5Hz, 2H), 2.28-2.07 (m, 2H), 1.21 (t, J=7.6Hz, 3H) (two phosphate protons do not measure)
Embodiment 418:
Biphosphate (S) -1- (6- (((R) -2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- Ethylpyridine -2- base) pyrrolidin-3-yl ester
Step 1:(S) the chloro- 4- ethyl -6- of -2- (3- hydroxyl pyrrolidine -1- base) pyridine -3,5- dimethoxy nitrile:
Under nitrogen at room temperature, to (S)-pyrrolidines -3- alcohol, hydrochloride (54.7g, 442mmol) is at methylene chloride (DCM) TEA (154mL, 1106mmol) and 2 is added in agitating solution in (3000mL), chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 6- bis- (synthesis, 100g, 442mmol are described in embodiment 3, step 2).Gained reaction mixture is stirred at room temperature 2 hours.It will The reaction mixture is diluted with water (2000mL) and is extracted with DCM (2x 2000mL).By combined organic layer water (2X 2000mL), saline solution (1000mL) washs, and uses anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure, obtain crude material.It should Crude material is ground with ether (1000mL), is filtered, dry, obtains the chloro- 4- ethyl -6- of (S) -2- (3- hydroxyl pyrrolidine -1- Base) pyridine -3,5- dimethoxy nitrile (110g, 89%) is Light brown solid.LCMS m/z=277.1 [M+H]+。
Step 2: phosphoric acid (S)-(1- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) pyrrolidin-3-yl) ester two - The tert-butyl ester:
In room temperature, to the chloro- 4- ethyl -6- of (S) -2- (3- hydroxyl pyrrolidine -1- base) pyridine -3,5- dimethoxy nitrile (160g, 1H-TETRAZOLE (81g, 1156mmol) and two-uncles 578mmol) are added in the agitating solution in tetrahydrofuran (THF) (1500mL) Butyl diethyl phosphoramidite (202g, 809mmol).The reaction mixture is stirred at room temperature 1 hour.Gained is reacted and is mixed Object is cooled to 0 DEG C, is then added dropwise to 2- peroxide hydrogen-based -2- methylpropane (145mL, 867mmol) in the reaction mixture simultaneously It is stirred at room temperature 1 hour.The reaction mixture is quenched with saturation solution of sodium bisulfite (1.5L) and with ethyl acetate (3x 1.5L) extract.Combined organic layer water (1.0L), saline solution (1.0L) are washed, Na is used2SO4It dries, filters and depressurizes Concentration, obtains crude material.The crude material neutral aluminum oxide column chromatography purified to (eluant, eluent: the hexane of 20%EtOAc is molten Liquid), obtain phosphoric acid (S)-(1- (chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-) pyrrolidin-3-yl) two-tert-butyl ester of ester (125g, 46%), is pale solid.LCMS m/z=469.2 [M+H]+。
Step 3:4- toluenesulfonic acid (S) -2- amino -2- oxo -1- phenylethylester
In room temperature, to (S) -2- hydroxyl -2- phenyl-acetamides (30g, 198mmol) in Isosorbide-5-Nitrae-dioxanes (300mL) DIPEA (104mL, 595mmol) and DMAP (2.425g, 19.85mmol) are added in agitating solution.The reaction mixture is cooling To 0 DEG C, then Ts-Cl (56.8g, 298mmol) is added in the reaction mixture and by the reaction mixture in batches in room temperature Stirring 16 hours.By the reaction mixture down to ice cold water (2000mL), stirs 10min and solid is precipitated.By the solid of precipitation It is collected by filtration and dries, obtain the crude compound.The crude material is ground with ether (2x 500mL), obtains 4- first Base benzene sulfonic acid (S) -2- amino -2- oxo -1- phenylethylester (38g, 58%), is pale solid.LCMS m/z= 306.1[M+H]+。
Step 4: phosphoric acid (S) -1- (6- (((R) -2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano - 4- ethylpyridine -2- base) pyrrolidin-3-yl ester di-t-butyl ester
In room temperature, to phosphoric acid (S)-(1- (chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-) pyrrolidin-3-yl) ester Thio second is added in the agitating solution in n,N-Dimethylformamide (DMF) (400mL) in the two-tert-butyl esters (40.0g, 84mmol) Sour potassium (14.46g, 127mmol) is simultaneously stirred at room temperature 2 hours.In room temperature, by TEA (17.65mL, 127mmol) and 4- methylbenzene Sulfonic acid (S) -2- amino -2- oxo -1- phenylethylester (28.1g, 84mmol) adds in the reaction mixture and stirring 18 is small When.The reaction mixture is diluted with ice cold water (2000mL) and is extracted with EtOAc (3x 1500mL).By combined organic layer It is washed with ice cold water (3x 2000mL), saline solution (1000mL), uses anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure, obtain Crude material.Crude material ether (200mL) and pentane (1000mL) are ground, filtered, it is dry, it is solid to obtain light brown Body.The solid material is dissolved in EtOAc (500mL) and is passed throughFiltering.The filtrate is concentrated under reduced pressure, phosphorus is obtained Acid (S) -1- (6- (((R) -2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) pyrrole Alkane -3- base ester di-t-butyl ester (38.0g, 59%) is coughed up, is Light brown solid.LCMS m/z=600.3 [M+H]+。
Step 5: biphosphate (S) -1- (6- (((R) -2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyan Base -4- ethylpyridine -2- base) pyrrolidin-3-yl ester
At 0 DEG C, to phosphoric acid (S) -1- (6- (((R) -2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyan Base -4- ethylpyridine -2- base) pyrrolidin-3-yl ester di-t-butyl ester (38.0g, 50.2mmol) is in ethyl alcohol (400mL) and second The diethyl ether solution of 2.0M hydrochloric acid (400mL, 800mmol) is added in agitating solution in ether (800mL).The reaction mixture is existed It is stirred at room temperature 2 hours.The reaction mixture is concentrated under reduced pressure, crude material is obtained.By the crude material and EtOH (400mL) and ether (800mL) condistillation (3 times), it is dry, obtain Light brown solid.By the solid material with EtOH (400mL) It grinds, filters with ether (800mL), it is dry, obtain biphosphate (S) -1- (6- (((R) -2- amino -2- oxo -1- phenyl second Base) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) pyrrolidin-3-yl ester (18.5g, 75%) is pale solid. LCMS (m/z): 488.0 [M+H]+。
Step 6: biphosphate (S) -1- (6- (((R) -2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyan Base -4- ethylpyridine -2- base) pyrrolidin-3-yl ester
By biphosphate (S) -1- (6- (((R) -2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- of two batches Dicyano -4- ethylpyridine -2- base) pyrrolidin-3-yl ester (4.7g and 18.5g) merge and be dissolved in ethyl alcohol (4.0L).This is molten Liquid evaporates under reduced pressure, obtains pale solid.By the solid material mixture (200mL:1000mL) of EtOH and ether Grinding is filtered, dry, obtains pale solid.Solid mortar and pestle are thoroughly ground, biphosphate (S) -1- is obtained (6- (((R) -2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) pyrrolidines -3- Base ester (22.5g, 98%), is pale solid.LCMS (m/z)=488.0 [M+H]+。1H NMR (400MHz, DMSO-d6)δ 7.88 (s, 1H), 7.52-7.48 (m, 2H), 7.40-7.23 (m, 4H), 5.59 (s, 1H), 4.92 (s, 1H), 4.05-3.96 (m, 2H), 3.95-3.82 (m, 2H), 2.73 (q, J=7.5Hz, 2H), 2.24-2.06 (m, 2H), 1.19 (t, J=7.6Hz, 3H). Two phosphate protons do not measure.
Embodiment 419:
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (3- (solutions of dimethyl phosphoryl Base) phenyl) acetamide
Step 1:3- (solutions of dimethyl phosphoryl base) benzonitrile:
By 3- iodine benzonitrile (4.9g, 21.40mmol), dimethyl phosphine (2.00g, 25.7mmol), PdOAc2 (0.240g, 1.070mmol), xanthene (0.62g, 1.07mmol) and potassium phosphate (5.45g, 25.7mmol) are in N, N- dimethyl methyl Mixture in amide (100mL) stirs 12 hours under 120 DEG C of nitrogen atmosphere.Then it is concentrated in vacuo to remove solvent.It will The residue with silicagel column (50g) purify, eluted with DCM:MeOH=20:1, obtain 3- (solutions of dimethyl phosphoryl base) benzonitrile (3.1g, 81% yield), it is white solid.LCMS m/z=180.1 [M+H]+。
Step 2:3- (solutions of dimethyl phosphoryl base) benzaldehyde:
By 3- (solutions of dimethyl phosphoryl base) benzonitrile (3g, 16.75mmol) and nickel (0.491g, 8.37mmol) in 88% formic acid Mixture in aqueous solution (100mL) stirs 7 hours under 125 DEG C of nitrogen atmosphere.After being cooled to room temperature, which is led to It crossesIt filters and is concentrated to dryness the filter vacuum.The residue is added into silicagel column (30g) and uses DCM:MeOH= 40:1 elution, obtains 3- (solutions of dimethyl phosphoryl base) benzaldehyde (3.4g, 100% yield, purity 90%), is yellow oil LCMS m/z=183.0 [M+H]+。
Step 3:2- (3- (solutions of dimethyl phosphoryl base) phenyl) -2- hydroxyl acetamide:
By 3- (solutions of dimethyl phosphoryl base) benzaldehyde (3.27g, 17.95mmol) and potassium phthalimide (0.665g, 3.59mmol) mixture in trimethylsilyl cyanide (50mL) stirs 14 hours at 20 DEG C.Then the reaction mixture is true Sky is concentrated to dryness.The residue is added into silicagel column (30g) and is eluted with DCM:MeOH=40:1, brown oil (2.8g) is obtained. By the brown oil (1.4g), palladium chloride (II) (0.190g, 1.071mmol) and acetamide (3.16g, 53.5mmol) in tetrahydro furan Mutter (30mL) and water (10mL) in mixture 20 DEG C stir 14 hours.Then it is concentrated in vacuo to dry.By the residue It adds to silicagel column (30g) and is eluted with DCM:MeOH=10:1, obtain 2- (3- (solutions of dimethyl phosphoryl base) phenyl) -2- hydroxyl acetyl Amine (1.8g), is brown oil.LCMS m/z=228.1 [M+H]+。
Step 4: methanesulfonic acid 2- amino -1- (3- (solutions of dimethyl phosphoryl base) phenyl) -2- oxoethyl ester:
At 0 DEG C, MsCl (0.274mL, 3.52mmol) is added dropwise to 2- (3- (solutions of dimethyl phosphoryl base) phenyl) -2- hydroxyl Acetamide (800mg, 3.52mmol) and TEA (0.982mL, 7.04mmol) are in methylene chloride (15mL) and N, N- dimethyl formyl In the mixture of stirring in amine (15mL).The mixture is stirred 3 hours at 0 DEG C.Then the reaction mixture vacuum is dense It is reduced to dry.The residue is added in silicagel column (30g) and uses CH2Cl2: MeOH=10:1 elution obtains methanesulfonic acid 2- amino- 1- (3- (solutions of dimethyl phosphoryl base) phenyl) -2- oxoethyl ester (2.7g, 76% yield, 30% purity), is yellow oil.LCMS M/z=305.9 [M+H]+。
Step 5:2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (3- (diformazan Base phosphoryl) phenyl) acetamide
2- (dimethylamino) -4- ethyl -6- mercaptopyridine -3,5- dimethoxy nitrile (is described in embodiment 92, step 3 Synthesis, 260mg, 1.119mmol), methanesulfonic acid 2- amino -1- (3- (solutions of dimethyl phosphoryl base) phenyl) -2- oxoethyl ester The mixture of (410mg, 1.343mmol) and TEA (0.468mL, 3.36mmol) in n,N-Dimethylformamide (25mL) exists 45 DEG C are stirred 14 hours.Then it is concentrated in vacuo to remove solvent.The residue is added into silicagel column (30g) and uses CH2Cl2: MeOH=15:1 elution, obtains crude product and (CH is further purified by preparative-TLC2Cl2: MeOH=15:1), obtain 2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (3- (solutions of dimethyl phosphoryl base) phenyl) second Amide (126mg, 25%), is yellow solid.LCMS m/z=442.2 [M+H]+。1H NMR (400MHz, CD3OD)δppm 7.97 (d, J=12.3Hz, 1H), 7.80-7.75 (m, 2H), 7.62-7.57 (m, 1H), 5.70 (s, 1H), 3.40 (s, 6H), 2.88 (q, J=7.6Hz, 2H), 1.82 (s, 3H), 1.79 (s, 3H), 1.29 (t, J=7.6Hz, 3H).
Embodiment 420:
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (3- (solutions of dimethyl phosphoryl base) phenyl) acetamide
By the chloro- 4- ethyl -6- of (S) -2- (3- hydroxyl pyrrolidine -1- base) pyridine -3,5- dimethoxy nitrile (in embodiment 418, Synthesis, 350mg, 1.27mmol are described in step 1) and thioacetic acid potassium (159mg, 1.39mmol) in N, N- dimethyl formyl Mixture in amine (30mL) stirs 0.5 hour at 20 DEG C.Then methanesulfonic acid 2- amino -1- (3- (solutions of dimethyl phosphoryl base) is added Phenyl) -2- oxoethyl ester (describing synthesis, 425mg, 1.39mmol in 419 step 4 of embodiment) and TEA (0.529mL, 3.79mmol), which is stirred 24 hours at 20 DEG C.Then it is concentrated in vacuo to remove solvent.The residue is added To silicagel column (30g) and use CH2Cl2: MeOH=15:1 elution obtains crude product and is further purified with preparative-TLC (CH2Cl2/ MeOH=15/1), obtain 2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- Base) sulfenyl) -2- (3- (solutions of dimethyl phosphoryl base) phenyl) acetamide (103mg, 17% yield) is gray solid.LCMS m/z =484.1 [M+H]+。1H NMR (400MHz, CD3OD) δ ppm 7.98 (d, J=12.2Hz, 1H), 7.81-7.74 (m, 2H), 7.62-7.58 (m, 1H), 5.71 (s, 1H), 4.53 (m, 1H), 3.93-3.84 (m, 4H), 2.87 (q, J=7.6Hz, 2H), 2.10-2.06 (m, 2H), 1.82 (s, 3H), 1.79 (s, 3H), 1.28 (t, J=7.6Hz, 3H).
Embodiment 421:
Biphosphate (R) -2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl Pyridine -2- base) (methyl) amino) ethyl ester:
Step 1:2- ((3,5- dicyano -4- ethyl -6- ((2- hydroxyethyl) (methyl) amino) pyridine -2- base) sulphur Base) -2- phenyl-acetamides:
At 0 DEG C, to chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (such as embodiment 3 synthesizes described in step 2, 75.0g, 0.332mol) and TEA (46mL, 0.332mol) 2- (methylamino) ethyl alcohol is added dropwise in the solution in DCM (1.5L) (24.9g, 0.332mol).1h is stirred at room temperature in acquired solution.Water is added and extracts the mixture with DCM (3x 500mL) It takes.By combined organic layer MgSO4It dries, filters and is concentrated in vacuo.The residue column chromatography is purified into (silica gel, PE/EA =3/1) the chloro- 4- ethyl -6- of 2- ((2- hydroxyethyl) (methyl) amino) pyridine -3,5- dimethoxy nitrile (74.0g, 84%), is obtained, It is white solid.LCMS (m/z)=264.9 [M+H]+.By the chloro- 4- ethyl -6- of 2- ((2- hydroxyethyl) (methyl) amino) The solution of pyridine -3,5- dimethoxy nitrile (71.3g, 0.269mol) and KSAc (35.9g, 0.315mol) in DMF (1L) is in room temperature Stir 1h.Then be added methanesulfonic acid 2- amino -2- oxo -1- phenylethylester (such as embodiment 3 synthesizes described in step 5, 72.1g, 0.315mol) and TEA (74.8mL, 0.538mol).Gained mixture is stirred at room temperature overnight and is concentrated under reduced pressure.It will The residue is dissolved in EA (1L) and is washed with water (3x500mL).By organic layer drying and it is concentrated in vacuo.By residue column color Spectrum purifying (silica gel, DCM/MeOH=50/1), obtains 2- (3,5- dicyano -4- ethyl -6- ((2- hydroxyethyl) (methyl) ammonia Base) pyridine -2- base sulfenyl) -2- phenyl-acetamides (32.0g, 30%) are white solid.LCMS (m/z)=396.1 [M+H ]+。
Step 2: biphosphate 2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- second Yl pyridines -2- base) (methyl) amino) ethyl ester:
At 0 DEG C, to 2- (3,5- dicyano -4- ethyl -6- ((2- hydroxyethyl) (methyl) amino) pyridine -2- base sulphur Base) -2- phenyl-acetamides (12.45g, 31.5mmol) and TEA (13.2mL, 94.6mmol) mixing in anhydrous THF (200mL) POCl is added dropwise in suspension3(14.5g, 94.6mmol).By gained mixture in 0 DEG C of stirring 1h.Ice is slowly added to so that this is quenched It reacts and extracts gained mixture with EA (3x 300mL).Combined organic layer is dried, filtered and is concentrated under reduced pressure.This is residual Excess column chromatography is purified (silica gel, MeOH/DCM=1:20), and crude product is obtained.Raw product is dissolved in acetone and is added dropwise to water In.The precipitating is filtered, drying is simultaneously recrystallized with Me-CN, obtains biphosphate 2- ((6- (2- amino -2- oxo -1- phenyl second Base sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) amino) ethyl ester (8g, 53%) is yellow solid. LCMS (m/z)=475.9 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 8.27 (s, 1H), 7.57 (d, J=8.0Hz, 2H), 7.39-7.30 (m, 4H), 5.67 (s, 1H), 4.05 (s, 2H), 4.00 (d, J=4Hz, 2H), 3.43 (s, 3H), 2.76 (q, J=8Hz, 2H), 1.20 (t, J=8Hz, 3H), 2 phosphate protons are not split completely.
Step 3: biphosphate (R) -2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano - 4- ethylpyridine -2- base) (methyl) amino) ethyl ester:
By biphosphate 2- ((6- (2- amino -2- oxo -1- phenylethyl sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) (methyl) amino) ethyl ester (1.987g) be dissolved in heat 1:1 heptane/EtOH in, containing several drop MSA be used for dissolve, Then positive HPLC chiral separation is carried out, 75:25:0.1 heptane mixture (95:5:.1 heptane: ethyl alcohol: methanesulfonic acid is used (MSA))；EtOH mixture (5:95:0.1 heptane: EtOH:MSA)；0.1MSA is on 30x250mm AD-H column.It is removed in vacuum molten After agent, which is dissolved in EtOAc, is washed twice with water, uses Na2SO4It dries, filters and is concentrated, obtain the peak of 741.2mg 2.LCMS (m/z)=476.1 [M+H]+。1H NMR (400MHz, methanol-d4) δ ppm 7.51-7.61 (m, 2H), 7.31-7.46 (m, 3H), 5.55 (s, 1H), 4.22-4.30 (m, 2H), 4.07-4.22 (m, 2H), 3.56 (s, 3H), 2.92 (q, J= 7.60Hz, 2H), 1.32 (t, J=7.60Hz, 3H).(S)-structure of the VCD and IR spectrum and simulation for the product that will be observed that It calculates spectrum to be compared, absolute configuration is designated as biphosphate (R) -2- ((6- ((2- amino -2- oxo -1- phenyl second Base) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) amino) ethyl ester.
Embodiment 422:
(R) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) - 2- (4- methoxyphenyl) acetamide
Step 1:2- hydroxyl -2- (4- methoxyphenyl) methyl acetate
At 0 DEG C, to stirring of 2- hydroxyl -2- (4- methoxyphenyl) acetic acid (5g, 27.4mmol) in methanol (50mL) Chloroacetic chloride (5.85mL, 82mmol) is added in solution.16h is stirred at room temperature in gained reaction mixture.The reaction is being depressurized Lower concentration obtains crude 2- hydroxyl -2- (4- methoxyphenyl) methyl acetate (5.1g, 14.63mmol, 53.3% yield), It is pale solid.Using the thick material without being further purified.LCMS (m/z)=195.02 [M-H]-。
Step 2:2- hydroxyl -2- (4- methoxyphenyl) acetamide
In RT, to 2- hydroxyl -2- (4- methoxyphenyl) methyl acetate (5.1g, 26.0mmol) in methanol (50mL) Ammonium hydroxide (25mL, 173mmol) is added and stirs 16h in RT.The reaction mixture is concentrated under reduced pressure, crudeization is obtained Close object.By the solid material with ether (200mL) grind, obtain 2- hydroxyl -2- (4- methoxyphenyl) acetamide (4.5g, 16.44mmol, 63.2% yield), it is pale solid.LCMS (m/z)=182.07 [M+H]+。
Step 3: methanesulfonic acid 2- amino -1- (4- methoxyphenyl) -2- oxoethyl ester
In room temperature, to 2- hydroxyl -2- (4- methoxyphenyl) acetamide (2g, 11.04mmol) at methylene chloride (DCM) TEA (4.62mL, 33.1mmol) is added in agitating solution in (40mL).The reaction mixture is cooled to 0 DEG C, then by first Sulfonic acid chloride (1.290mL, 16.56mmol) adds to the reaction mixture in batches.1h is stirred at room temperature in the reaction mixture.It will be anti- Mixture is answered to be quenched with water (100mL) and extracted with DCM (2X100mL).By the anhydrous sodium sulfate drying of combined organic layer, mistake Filter, then evaporates under reduced pressure, obtains crude methanesulfonic acid 2- amino -1- (4- methoxyphenyl) -2- oxoethyl ester (1.8g, 6.60mmol, 59.7% yield), is faint yellow solid.1H NMR (400MHz, DMSO-d6): δ ppm 7.41 (s, 1H), 7.29 (d, J=8.55Hz, 2H), 7.17 (s, 1H), 6.90 (d, J=8.77Hz, 2H), 4.47 (s, 1H), 3.74 (s, 3H), 3.24 (s, 3H).
Step 4:2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulphur Base) -2- (4- methoxyphenyl) acetamide
In room temperature, (implementing to the chloro- 4- ethyl -6- of (S) -2- (3- hydroxyl pyrrolidine -1- base) pyridine -3,5- dimethoxy nitrile Synthesis, 1.5g, 5.30mmol are described in 418 step 1 of example) stirring in n,N-Dimethylformamide (DMF) (30mL) is molten Thioacetic acid potassium (1.210g, 10.60mmol) is added in liquid.2h is stirred at room temperature in the reaction.Then in room temperature by TEA (1.477mL, 10.60mmol) and methanesulfonic acid 2- amino -1- (4- methoxyphenyl) -2- oxoethyl ester (1.880g, It 6.89mmol) adds to the reaction mixture and stirs 3h.The reaction mixture water (100mL) is diluted and uses EtOAc (3x100mL) extraction.Combined organic layer is dried, filtered with anhydrous sodium sulfate, is concentrated under reduced pressure.By the crude material positive Chromatogram purification (silica gel, 40 μm, flow velocity 40ml/min) purifies instrument using Grace Reveleris, passes through the DCM of 4%MeOH Solution elution, obtains 2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) - 2- (4- methoxyphenyl) acetamide (1.6g, 3.64mmol, 68.6% yield), is pale solid.LCMS (m/z)= 438.1[M+H]+。
Step 5:(R) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) Sulfenyl) -2- (4- methoxyphenyl) acetamide
By 2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- The non-enantiomer mixture (1.6g, 3.66mmol) of (4- methoxyphenyl) acetamide passes through chirality SFC preparative-HPLC It separates (Chiralcel OJ-H (30x 250mm)), obtains peak -1 (R) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyls Base pyrrolidin-1-yl) pyridine -2- base) sulfenyl) -2- (4- methoxyphenyl) acetamide (220mg, 0.502mmol, 13.72% Yield), it is pale solid.The LCMS:m/z=438.08 [M+H] at peak -1+。1H NMR (400MHz, DMSO-d6): δ ppm 7.80 (s, 1H), 7.42 (d, J=8.77Hz, 2H), 7.22 (s, 1H), 6.93 (d, J=8.77Hz, 2H), 5.54 (s, 1H), 5.13 (d, J=3.51Hz, 1H), 4.48-4.38 (m, 1H), 3.98-3.79 (m, 4H), 3.74 (s, 3H), 2.75 (q, J= 7.67Hz, 2H), 2.07-1.86 (m, 2H), 1.20 (t, J=7.67Hz, 3H).Compare (R) -2- ((3,5- dicyano -4- second Base -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (4- methoxyphenyl) acetamide subtracts (S) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (4- methoxyphenyl) The VCD difference spectrum measured and (R)-of acetamide subtract the VCD difference spectrum of the calculating of (S)-, and the absolute configuration at peak 1 is designated For (R) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (4- first Phenyl) acetamide.
Embodiment 423:
(R) -2- ((6- ((R) -3- (amino methyl) -3- hydroxyl pyrrolidine -1- base) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) sulfenyl) -2- phenylacetyl amine hydrochlorate
Step 1:((1- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) -3- hydroxyl pyrrolidine -3- base) methyl) T-butyl carbamate:
To ((3- hydroxyl pyrrolidine -3- base) methyl) t-butyl carbamate (2.39g, 11.06mmol) in methylene chloride (DCM) TEA (4.62mL, 33.2mmol) is added in the agitating solution in (50mL) and is stirred at 26 DEG C.Then mutually synthermal Chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile (2.5g, 11.06mmol) of 2,6- bis- is added in the reaction mixture.The reaction is mixed Object is closed in 26 DEG C of stirring 16h.The reaction mixture is allocated between water (500mL) and DCM (2X 200mL).By having for merging Machine layer is dried, filtered by anhydrous sodium sulfate and evaporates filtrate, and crude material is obtained.By the crude material pentane and ether (1:1) washing, obtains ((1- (chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-) -3- hydroxyl pyrrolidine -3- base) methyl) ammonia Base t-butyl formate (4.0g, 88%), is pale solid.LCMS (m/z): 406.11 [M+H]+。
Step 2:((1- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) -3- hydroxyl pyrrolidine -3- base) methyl) T-butyl carbamate, single stereoisomers:
By ((1- (the chloro- 3,5- dicyano -4- ethylpyridine -2- base of 6-) -3- hydroxyl pyrrolidine -3- base) methyl) amino T-butyl formate carries out chirality SFC purifying (column: Lux Cellulose-2 (4.6x 250mm)) and respectively carries out obtained fractions It is concentrated under reduced pressure, obtains ((1- (chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-) -3- hydroxyl pyrrolidine -3- base) methyl) ammonia Base t-butyl formate (1.4g, 34.5%, peak -1), is pale solid, single unknown stereoisomer.LCMS (m/z): 406.20[M+H]+。
Step 3:((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) -3- hydroxyl pyrrolidine -3- base) methyl) t-butyl carbamate
Under 0 DEG C of nitrogen atmosphere, to ((1- (chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-) -3- hydroxyl pyrrolidine - 3- yl) methyl) t-butyl carbamate (1.35g, 3.23mmol, the peak -1 from preceding step) is in n,N-Dimethylformamide (DMF) thioacetic acid potassium (0.553g, 4.84mmol) is added in the agitating solution in (20mL).By the reaction mixture at 0 DEG C 1h is stirred, then in 0 DEG C of addition K2CO3(0.669g, 4.84mmol) and methanesulfonic acid 2- amino -2- oxo -1- phenylethylester (0.814g, 3.55mmol).By the reaction in 26 DEG C of stirring 16h.The reaction mixture is used in combination down to ice cold water (200mL) EtOAc (2X 150mL) extraction.Combined organic layer is dried, filtered and is concentrated under reduced pressure with anhydrous sodium sulfate, crude material is obtained Material.Crude material ether and pentane (1:1) are washed, ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulphur is obtained Base) -3,5- dicyano -4- ethylpyridine -2- base) -3- hydroxyl pyrrolidine -3- base) methyl) t-butyl carbamate (1.4g, It 74.0%), is faint yellow solid, the mixture of 2 diastereoisomers.LCMS (m/z): 537.05 [M+H]+。
Step 4:((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) -3- hydroxyl pyrrolidine -3- base) methyl) t-butyl carbamate, single diastereoisomer
By ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) -3- hydroxyl pyrrolidine -3- base) methyl) t-butyl carbamate (1.4g comes from above-mentioned steps) progress chirality SFC purifying (Chiralpak AD-H (30x250mm), acetonitrile/IPA).The obtained fractions at peak 2 are concentrated under reduced pressure, ((1- (6- is obtained ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) -3- hydroxyl pyrrolidine -3- Base) methyl) t-butyl carbamate (310mg, 23.65%, single diastereoisomer) is pale solid.LCMS(m/ Z): 537.25 [M+H]+。
Step 5:(R) -2- ((6- ((R) -3- (amino methyl) -3- hydroxyl pyrrolidine -1- base) -3,5- dicyano -4- second Yl pyridines -2- base) sulfenyl) -2- phenylacetyl amine hydrochlorate
At 0 DEG C, to ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) -3- hydroxyl pyrrolidine -3- base) methyl) (280mg, 0.510mmol are obtained t-butyl carbamate from preceding step The peak 2 arrived) dropwise addition TFA (0.196mL, 2.55mmol) in the agitating solution in methylene chloride (DCM) (10mL).Gained is anti- Answer mixture in 0 DEG C of stirring 1h.The progress of the reaction is monitored by TLC.The reaction mixture is evaporated under reduced pressure, is obtained thick Prepared material.Crude material ether and pentane (1:1) are washed, crude compound is obtained, is tfa salt.By the crude material Material is dissolved in ethyl alcohol (15mL) and the diethyl ether solution of the 2M HCl of 5mL is added.Acquired solution is concentrated in vacuo at 40 DEG C.The process weight It is 2 times multiple.The crude material is washed with normal heptane (30mL) and is then washed with ether (20mL), (R) -2- ((6- ((R)-is obtained 3- (amino methyl) -3- hydroxyl pyrrolidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides Hydrochloride (214mg, 85%), is faint yellow solid.The absolute configuration of the chiral centre adjacent with sulphur is analyzed by VCD and is confirmed LCMS (m/z): 437.14 [M+H]+。1H NMR (400MHz, DMSO-d6): δ ppm 8.45-7.88 (m, 4H), 7.58 (d, J= 7.02Hz, 2H), 7.47-7.18 (m, 4H), 5.87-5.64 (m, 2H), 4.16-3.83 (m, 4H), 3.2-3.05 (m, 2H), 2.75 (q, J=7.38Hz, 2H), 2.06 (d, J=6.14Hz, 2H), 1.28 (t, J=7.5Hz, 3H).
Embodiment 424:
(R) -2- (4- chlorphenyl) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyrrole Pyridine -2- base) sulfenyl) acetamide
Step 1:2- (4- chlorphenyl) -2- hydroxy methyl acetate:
At 0 DEG C, to agitating solution of 2- (4- the chlorphenyl) -2- hydroxyacetic acid (5g, 26.8mmol) in methanol (50mL) Middle addition chloroacetic chloride (5.72mL, 80mmol).5h is stirred at room temperature in the reaction mixture.The reaction process is supervised by TLC It controls and is concentrated under reduced pressure the reaction mixture to remove all volatile matters.Cold ethyl alcohol (15ml) is added into crude chemical combination Object stirs 5 minutes and filters, obtains 2- (4- chlorphenyl) -2- hydroxy methyl acetate (4.8g, 23.93mmol, 89% yield), It is pale solid.1H NMR (400MHz, DMSO-d6): δ ppm 7.48-7.39 (m, 4H), 6.00-5.32 (m, 1H), 5.18 (s, 1H), 3.67 (s, 3H).
Step 2:(S) -2- (4- chlorphenyl) -2- hydroxyl acetamide:
At 0 DEG C, to 2- (4- chlorphenyl) -2- hydroxy methyl acetate (4.7g, 23.43mmol) in methanol (50mL) Ammonium hydroxide (3.65mL, 23.43mmol) is added in agitating solution.16h is stirred at room temperature in the reaction mixture.By the reaction Process is monitored by TLC.The reaction mixture is concentrated under reduced pressure to remove all volatile matters.The thick material is dissolved in water And it is extracted with ethyl acetate (2x 50mL).By combined organic layer saturation NaHCO3Solution, aqueous salt solu-tion, use are anhydrous Sodium sulphate is dried, filtered and is concentrated, and obtains 2- (4- chlorphenyl) -2- hydroxyl acetamide (2.9g), is pale solid (hand Property-HPLC:49.14%, rt=2.79,50.88%, rt=3.4).By 2- (4- chlorphenyl) -2- hydroxyl acetamide (2.8g, (chiralpak AD-H (30x 250mm) column, MeOH) 14.98mmol) is further purified with chirality SFC preparative-HPLC, obtains It is pale solid to peak -2 (S) -2- (4- chlorphenyl) -2- hydroxyl acetamide (1.1g, 5.63mmol, 37.6% yield). LCMS (m/z): 184.0 [M-H]-.Peak -2: in 28 DEG C of [α]D=+86.13 (c2, acetone), > 98%ee.
Step 3:4- toluenesulfonic acid (S) -2- amino -1- (4- chlorphenyl) -2- oxoethyl ester:
Under 0 DEG C of nitrogen, to (S) -2- (4- chlorphenyl) -2- hydroxyl acetamide (0.400g, 2.150mmol) in Isosorbide-5-Nitrae - In stirring suspension in dioxanes (10mL) be added DIPEA (1.127mL, 6.45mmol), DMAP (0.263g, 2.150mmol) and paratoluensulfonyl chloride (0.615g, 3.23mmol).16h is stirred at room temperature in the reaction mixture.This is anti- Process is answered to monitor by TLC.The reaction mixture down to ice cold water (20mL) and is stirred 10 minutes.The solid of precipitation is filtered And drying.The thick material is washed with ether (2X 20mL), obtains 4- toluenesulfonic acid (S) -2- amino -1- (4- chlorphenyl) - 2- oxoethyl ester (0.330g, 44.6% yield), is pale solid.LCMS (m/z): 339.99 [M+H]+。
Step 4:(R) -2- (4- chlorphenyl) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- Base) pyridine -2- base) sulfenyl) acetamide:
In room temperature, (implementing to the chloro- 4- ethyl -6- of (S) -2- (3- hydroxyl pyrrolidine -1- base) pyridine -3,5- dimethoxy nitrile Synthesis, 0.250g, 0.872mmol are described in 418 step 1 of example) solution in n,N-Dimethylformamide (DMF) (10mL) Middle addition thioacetic acid potassium (0.199g, 1.743mmol).By the mixture in mutually synthermal stirring 2h.Reaction progress is logical Cross TLC monitoring (50% ethyl acetate: petroleum ether, rf:0.5, UV activity).Room temperature be added triethylamine (0.243mL, 1.743mmol) and 4- toluenesulfonic acid (S) -2- amino -1- (4- chlorphenyl) -2- oxoethyl ester (0.300g, 0.872mmol) and 4h is stirred at room temperature.By reaction progress, by TLC monitoring, (50%EtOAc/ petroleum ether, Rf:0.4, UV are living Property).The reaction mixture is extracted down in ice water (30ml) and with ethyl acetate (3X 40ml).Combined organic layer is used Saline solution and cold water washing.By organic layer anhydrous Na2SO4It dries, filters and is concentrated under reduced pressure.By the crude compound with penta Alkane (2X30ml) and ether (2X 20ml) washing, obtain (R) -2- (4- chlorphenyl) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) acetamide (0.160g, 0.356mmol, 40.8% yield), For Light brown solid.It will be observed that VCD the and IR spectrum of product and the calculating spectrum of two kinds of possible structures of simulation compared Compared with, it was demonstrated that the absolute configuration of the chiral centre adjacent with sulphur is (R)-.LCMS (m/z): 440.08 [M-H]-。1H NMR (400MHz, DMSO-d6): δ ppm 7.93 (s, 1H), 7.54 (d, J=8.10Hz, 2H), 7.44 (d, J=8.55Hz, 2H), 7.33 (s, 1H), 5.63 (s, 1H), 5.13 (d, J=3.6Hz, 1H), 4.48-4.38 (m, 1H), 3.99-3.64 (m, 4H), 2.74 (q, J=7.5Hz, 2H), 2.05-1.87 (m, 2H), 1.20 (t, J=7.6Hz, 3H).
Embodiment 425:
(R) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) - 2- (4- fluorophenyl) acetamide
Step 1:2- (4- fluorophenyl) -2- hydroxyl acetamide, single stereoisomers
By 2- (4- fluorophenyl) -2- hydroxyl acetamide (describe synthesis in embodiment 207, step 2,4.0g, 23.41mmol) carry out chirality SFC HPLC (Chiralpak-AS-H ((30x 250mm) column).By the pure fraction decompression Concentration, obtains 2- (4- fluorophenyl) -2- hydroxyl acetamide (peak 2,1.56g, 9.14mmol, 39.0% yield), solid for white Body LCMS m/z=167.99 [M-H]-.
Step 2: methanesulfonic acid 2- amino -1- (4- fluorophenyl) -2- oxoethyl ester, single stereoisomers
At 0 DEG C, to 2- (4- fluorophenyl) -2- hydroxyl acetamide (1.0g, the 5.85mmol, in abovementioned steps of chiral purity Peak 2) be added in the agitating solution in DCM (10mL) TEA (2.44mL, 17.56mmol) and methane sulfonyl chloride (0.9mL, 11.71mmol).1h is stirred at room temperature in the mixture.The reaction mixture is diluted with water (100mL) and with DCM (3x 100mL) extract.Combined organic layer water (100mL), saline solution (100mL) are washed and use anhydrous Na2SO4It is dry, mistake It filters and is concentrated under reduced pressure.The crude material is ground with pentane (100mL), filters and is dried in vacuo, obtain methanesulfonic acid 2- amino- 1- (4- fluorophenyl) -2- oxoethyl ester, single stereoisomers (0.95g, 61.6%), are pale solid.LCMS(m/ Z)=248.00 [M+H]+。
Step 3:(R) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) Sulfenyl) -2- (4- fluorophenyl) acetamide
In room temperature, (implementing to the chloro- 4- ethyl -6- of (S) -2- (3- hydroxyl pyrrolidine -1- base) pyridine -3,5- dimethoxy nitrile Example 418 describes synthesis, 650mg, 2.29mmol in step 1) stirring in n,N-Dimethylformamide (DMF) (30mL) Thioacetic acid potassium (294mg, 2.52mmol) is added in solution.2h is stirred at room temperature in the mixture.Addition TEA (0.65mL, 4.58mmol) and above-mentioned steps in methanesulfonic acid 2- amino -1- (4- fluorophenyl) -2- oxoethyl ester (0.694g, 2.63mmol).The reaction mixture in room temperature and is stirred into 16h.The reaction mixture ice cold water (150mL) is diluted and stirred Mix 10min.The solid of precipitation is filtered and is dried in vacuo.By the crude material ether: acetonitrile (10:1 (2x30mL)) is ground, It filters and is dried in vacuo, obtain (R) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- Base) sulfenyl) -2- (4- fluorophenyl) acetamide (420mg, 42.3mmol) is pale solid.LCMS (m/z)=426.13 [M+H]+。1H NMR (400MHz, DMSO-d6): δ 7.90 (s, 1H), 7.67-7.48 (m, 2H), 7.30 (s, 1H), 7.27-7.03 (m, 2H), 5.62 (s, 1H), 5.13 (d, J=3.5Hz, 1H), 4.44-4.38 (m, 1H), 3.89-3.67 (m, 4H), 2.74 (q, J=7.5Hz, 2H), 2.16-1.86 (m, 2H), 1.20 (t, J=7.6Hz, 3H).Compare (S) -2- ((3,5- dicyano -4- second Base -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (4- fluorophenyl) acetamide and (R) -2- ((3,5- Dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (4- fluorophenyl) acetamide sight The VCD difference observed, is the VCD difference between the reference compound of two kinds of previous analysis, and the absolute configuration of the material is referred to It is set to (R) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (4- Fluorophenyl) acetamide.
Embodiment 426:
Biphosphate (S) -1- (6- (((R) -2- amino -1- (4- fluorophenyl) -2- oxoethyl) sulfenyl) -3,5- dicyan Base -4- ethylpyridine -2- base) pyrrolidin-3-yl esterStep 1: phosphoric acid (S) -1- (6- (((R) -2- amino -1- (4- fluorophenyl) - 2- oxoethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) pyrrolidin-3-yl ester di-t-butyl ester
In room temperature, to phosphoric acid (S)-(1- (chloro- 3, the 5- dicyano -4- ethylpyridine -2- base of 6-) pyrrolidin-3-yl) ester Two-the tert-butyl esters (synthesis, 0.6g, 1.26mmol are described in embodiment 418, step 2) are at n,N-Dimethylformamide (DMF) Thioacetic acid potassium (148mg, 1.26mmol) is added in agitating solution in (25mL).2h is stirred into the reaction.Then in room temperature By TEA (0.27mL, 1.9mmol) and methanesulfonic acid 2- amino -1- (4- fluorophenyl) -2- oxoethyl ester (in embodiment 425, step Synthesis, 348mg, 1.39mmol are described in rapid 2) it adds in the reaction mixture and stirs 16h.By the reaction mixture ice Cold water (100mL) dilutes and stirs 30min.The solid is filtered, is washed and is dried in vacuo with water (300mL), obtain phosphoric acid (S) -1- (6- (((R) -2- amino -1- (4- fluorophenyl) -2- oxoethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) pyrrolidin-3-yl ester di-t-butyl ester (0.86g, 85%) LCMS (m/z)=618.26 [M+H]+。
Step 4: biphosphate (S) -1- (6- (((R) -2- amino -1- (4- fluorophenyl) -2- oxoethyl) sulfenyl) -3, 5- dicyano -4- ethylpyridine -2- base) pyrrolidin-3-yl ester
At 0 DEG C, to phosphoric acid (S) -1- (6- (((R) -2- amino -1- (4- fluorophenyl) -2- oxoethyl) sulfenyl) -3,5- Dicyano -4- ethylpyridine -2- base) pyrrolidin-3-yl ester di-t-butyl ester (0.850g, 1.05mmol) is in ethyl alcohol (5mL) Agitating solution in be added 2.0M hydrochloric acid (10.59mL, 20.23mmol) diethyl ether solution.The reaction mixture is stirred in room temperature 2h is mixed, is then concentrated under reduced pressure.The crude material mixture of EtOH (10mL) and ether (30mL) is ground.This is consolidated Body filtering, is washed and is dried in vacuo with excessive ether (200mL), obtain biphosphate (S) -1- (6- (((R) -2- amino -1- (4- fluorophenyl) -2- oxoethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) pyrrolidin-3-yl ester (290mg, It 53.2%), is orange solids.LCMS (m/z)=506.21 [M+H]+。1H NMR (400MHz, DMSO-d6): δ ppm 8.01 (s, 1H), 7.60-7.53 (m, 2H), 7.28 (s, 1H), 7.20 (t, J=8.77Hz, 2H), 5.64 (s, 1H), 4.96-4.90 (m, 1H), 3.87-4.10 (m, 4H), 2.74 (q, J=7.67Hz, 2H), 2.26-2.07 (m, 2H), 1.19 (t, J=7.56Hz, 3H), 2 protons are not split completely.Based on (S) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) Pyridine -2- base) sulfenyl) -2- (4- fluorophenyl) acetamide and (R) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrole Cough up alkane -1- base) pyridine -2- base) sulfenyl) and -2- (4- fluorophenyl) acetamide the VCD difference, i.e. two kinds of references being previously separated Compound, the absolute configuration of the material are designated as biphosphate (S) -1- (6- (((R) -2- amino -1- (4- fluorophenyl) -2- Oxoethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) pyrrolidin-3-yl ester.
Embodiment 427:
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (4- Fluorophenyl) acetamide
In room temperature, (implementing to the chloro- 4- ethyl -6- of (S) -2- (3- hydroxyl pyrrolidine -1- base) pyridine -3,5- dimethoxy nitrile Synthesis, 550mg, 1.789mmol are described in 418 step 1 of example) stirring in n,N-Dimethylformamide (DMF) (10mL) Thioacetic acid potassium (204mg, 1.789mmol) is added in solution.By the reaction mixture in mutually synthermal stirring 2h.Then in room Potassium carbonate (247mg, 1.789mmol) is added in temperature, and methanesulfonic acid 2- amino -1- (4- fluorophenyl) -2- oxoethyl ester is then added (describing synthesis, 750mg, 2.022mmol in 207 step 3 of embodiment).The reaction mixture is stirred into 2h.By the reaction Mixture is quenched with cold water (50mL) and filters obtained solid, is washed and is dried in vacuo with ether (2x 20mL), obtained crude Material.The diethyl ether solution (30mL) of 10% methanol of the crude material is ground, is then ground with pentane (30mL), is obtained thick Prepared material.By the crude compound by silica gel chromatography (100-200 mesh is eluted with the DCM solution of 4%MeOH), obtain To 2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (4- fluorophenyl) Acetamide (300mg, 38.7%), is pale solid.LCMS (m/z)=426.00 [M+H]+。1H NMR (400MHz, DMSO-d6): δ ppm 7.90 (s, 1H), 7.58-7.52 (m, 2H), 7.30 (s, 1H), 7.21 (t, J=8.77Hz, 2H), 5.65-5.62 (m, 1H), 5.14-5.11 (m, 1H), 4.43-4.40 (m, 1H), 4.02-3.65 (m, 4H), 2.74 (q, J= 7.67Hz, 2H), 2.07-1.85 (m, 2H), 1.20 (t, J=7.56Hz, 3H).
Embodiment 428:
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (2, 6- difluorophenyl) acetamide
Step 1:2- (2,6- difluorophenyl) -2- hydroxyacetonitrile
In room temperature, it is added in the agitating solution in DCM (40mL) to 2,6- difluorobenzaldehyde (2.0g, 13.79mmol) Then zinc iodide (0.889g, 2.76mmol) is added in TMS-CN (3.77mL, 27.6mmol).By the reaction mixture in room temperature Stir 1h.The reaction mixture is diluted with DCM (200mL) and is washed with water (50mL), is dried, filtered simultaneously with anhydrous sodium sulfate It is concentrated under reduced pressure, obtains crude 2- (2,6- difluorophenyl) -2- ((trimethyl silyl) oxygroup) acetonitrile (2.5g, 75%), It is crude yellow liquid.It is used without being further purified.In room temperature, to 2- (2,6- difluorophenyl) -2- ((trimethyl first Silylation) oxygroup) acetonitrile (2.3g, 9.53mmol) be added in the agitating solution in DCM (30mL) hydrochloric acid (14.30mL, 28.6mmol) the solution in water (2M solution).30min is stirred at room temperature in the reaction mixture.The reaction process is passed through TLC monitoring.The reaction mixture is diluted with DCM (100mL) and is washed with water (50mL), is dried, filtered with anhydrous sodium sulfate And it is concentrated under reduced pressure.Crude material mixture of the ether (10mL) in petroleum ether (30mL) is ground, 2- (2,6- bis- is obtained Fluorophenyl) -2- hydroxyacetonitrile (1.5g, 93%) is yellow solid.1H NMR (400MHz, DMSO-d6): δ ppm 7.77- 7.41 (m, 1H), 7.29-7.08 (m, 3H), 5.93 (d, J=5.26Hz, 1H).
Step 2:2- (2,6- difluorophenyl) -2- hydroxyl acetamide
Under 0 DEG C of nitrogen atmosphere, to 2- (2,6- difluorophenyl) -2- hydroxyacetonitrile (1.4g, 8.28mmol) in methylene chloride (DCM) H is added in the stirring suspension in (20mL)2SO4(0.882mL, 16.56mmol).The reaction mixture is stirred at 0 DEG C Mix 1.5h.By reaction mixture NaHCO3Aqueous solution (70mL) is quenched and is extracted with ethyl acetate (3X 200mL).It will close And organic layer washed with salt water (100mL) solution, dried, filtered and be concentrated under reduced pressure with anhydrous sodium sulfate.By the crude material With ether (20mL) grind, filter and be dried in vacuo, obtain 2- (2,6- difluorophenyl) -2- hydroxyl acetamide (800mg, It 51.6%), is pale solid.1H NMR (400MHz, DMSO-d6): δ ppm 7.58-7.32 (m, 3H), 7.05 (t, J= 8.44Hz, 2H), 6.37 (d, J=5.48Hz, 1H), 5.16 (d, J=5.26Hz, 1H).
Step 3: methanesulfonic acid 2- amino -1- (2,6- difluorophenyl) -2- oxoethyl ester
Under 0 DEG C of nitrogen atmosphere, to 2- (2,6- difluorophenyl) -2- hydroxyl acetamide (800mg, 4.27mmol) in dichloro Triethylamine (1.216mL, 8.55mmol) and mesyl chloride are added in the suspension of stirring in methane (DCM) (15mL) (0.408mL, 5.13mmol).1h is stirred at room temperature in the reaction.The reaction mixture is diluted with water (50mL).Water layer is used Ethyl acetate (3X 100mL) extraction.Combined organic layer (only ethyl acetate) is dried, filtered and depressurized with anhydrous sodium sulfate Concentration, obtains methanesulfonic acid 2- amino -1- (2,6- difluorophenyl) -2- oxoethyl ester (0.98g, 77% yield), is light pink Color solid.LCMS (m/z)=266.06 [M+H]+。
Step 4:2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulphur Base) -2- (2,6- difluorophenyl) acetamide
In room temperature, (implementing to the chloro- 4- ethyl -6- of (S) -2- (3- hydroxyl pyrrolidine -1- base) pyridine -3,5- dimethoxy nitrile Synthesis, 0.90g, 2.93mmol are described in 418 step 1 of example) stirring in n,N-Dimethylformamide (DMF) (10mL) is molten Thioacetic acid potassium (0.512g, 4.39mmol) is added in liquid and by the reaction mixture in mutually synthermal stirring 2h.To the reaction Potassium carbonate (0.619g, 4.39mmol) and methanesulfonic acid 2- amino -1- (2,6- difluorophenyl) -2- oxoethyl ester is added in mixture Simultaneously 3h is stirred at room temperature in (0.872g, 2.93mmol).By the reaction mixture down to ice cold water (70mL) and with ethyl acetate (2x 200mL) extract.Combined organic layer water (100mL), saline solution (100mL) are washed, mistake dry with anhydrous sodium sulfate It filters and is concentrated under reduced pressure.By the crude material, by silica gel chromatography, (100-200 mesh is washed with the DCM solution of 4%MeOH It is de-), obtain Light brown solid.Light brown solid mixture of the methanol (1mL) in ether (15mL) is ground, 2- is obtained ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (2,6- difluorophenyl) Acetamide (148mg, 11.38%), is pale solid.LCMS (m/z)=444.07 [M+H]+。1H NMR (400MHz, DMSO-d6): δ ppm 7.59 (s, 1H), 7.55-7.41 (m, 2H), 7.16 (t, J=8.44Hz, 2H), 6.25-6.23 (m, 1H), 5.18-5.15 (m, 1H), 4.47-4.41 (m, 1H), 3.69-4.02 (m, 4H), 2.78 (q, J=7.53Hz, 2H), 1.87-2.12 (m, 2H), 1.22 (t, J=7.34Hz, 3H).
Embodiment 429:
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (2, 3- difluorophenyl) acetamide
Step 1:2- (2,3- difluorophenyl) -2- ((trimethyl silyl) oxygroup) acetonitrile
It is molten to stirring of 2, the 3- difluorobenzaldehyde (5g, 35.2mmol) in methylene chloride (DCM) (60mL) in room temperature Zinc iodide (2.246g, 7.04mmol) and TMS-CN (5.66mL, 42.2mmol are added in liquid.By the reaction mixture in room temperature Stir 3h.The reaction mixture is diluted with methylene chloride (50mL) and is washed with water (50mL), mistake dry with anhydrous sodium sulfate It filters and is concentrated under reduced pressure, obtain 2- (2,3- difluorophenyl) -2- ((trimethyl silyl) oxygroup) acetonitrile (5.1g, 54%).It will The crude material is used in next step without purification.GC-MS (m/z)=241.1 [M]+。
Step 2:2- (2,3- difluorophenyl) -2- hydroxyl acetamide
At 0 DEG C, to 2- (2,3- difluorophenyl) -2- ((trimethyl silyl) oxygroup) acetonitrile (6g, 24.86mmol) Sulfuric acid (5.325mL, 100mmol) is added in the agitating solution in methylene chloride (DCM) (60mL).By the mixture in room temperature Stir 2h.Then in 0 DEG C of addition ammonium hydroxide (10mL, 257mmol) and 2h is stirred at room temperature in gained mixture.By the reaction Mixture is diluted with methylene chloride (100mL) and is washed with water (50mL), is dried, filtered and is concentrated under reduced pressure with anhydrous sodium sulfate. The crude material is washed with pentane (3x 20mL), obtain 2- (2,3- difluorophenyl) -2- hydroxyl acetamide (1.1g, It 21%), is pale solid.LCMS (m/z)=188.04 [M+H]+。
Step 3: methanesulfonic acid 2- amino -1- (2,3- difluorophenyl) -2- oxoethyl ester
Under 0 DEG C of nitrogen atmosphere, to 2- (2,3- difluorophenyl) -2- hydroxyl acetamide (1g, 5.34mmol), TEA Mesyl chloride is added in the suspension of the stirring in methylene chloride (DCM) (15mL) in (2.234mL, 16.03mmol) (0.833mL, 10.69mmol).By gained mixture in 0 DEG C of stirring 3h.The reaction mixture is concentrated under reduced pressure, water is used (30mL) dilution is simultaneously extracted with methylene chloride (2X 100mL).Combined organic layer is dried, filtered and subtracted with anhydrous sodium sulfate Pressure concentration.By the crude material with ether (3X 20mL) grind, filter and be dried in vacuo, obtain methanesulfonic acid 2- amino -1- (2, 3- difluorophenyl) -2- oxoethyl ester (600mg, 21%) is pale solid.LCMS (m/z)=266.25 [M+H]+。
Step 4:2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulphur Base) -2- (2,3- difluorophenyl) acetamide
In room temperature, (implementing to the chloro- 4- ethyl -6- of (S) -2- (3- hydroxyl pyrrolidine -1- base) pyridine -3,5- dimethoxy nitrile Synthesis, 600mg, 1.930mmol are described in 418 step 1 of example) stirring in n,N-Dimethylformamide (DMF) (15mL) Thioacetic acid potassium (331mg, 2.89mmol) is added in solution and 2h is stirred at room temperature.Potassium carbonate is added into the reaction mixture (533mg, 3.86mmol) and methanesulfonic acid 2- amino -1- (2,3- difluorophenyl) -2- oxoethyl ester (563mg, 2.123mmol).After 16h is stirred at room temperature in the reaction mixture, it is diluted with water (20mL) and with ethyl acetate (2x 200mL) extract.Combined organic layer is dried, filtered and is concentrated under reduced pressure with anhydrous sodium sulfate.The crude material is passed through into silica gel Column chromatography purifies (100-200 mesh, eluant, eluent, the petroleum ether solution of 60% ethyl acetate), obtains 2- ((3,5- dicyano -4- second Base -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (2,3- difluorophenyl) acetamide (286mg, It 33.4%), is pale solid.LCMS (m/z)=444.13 [M+H]+。1H NMR (400MHz, DMSO-d6): δ ppm 7.91 (s, 1H), 7.52-7.39 (m, 2H), 7.37-7.30 (m, 1H), 7.29-7.19 (m, 1H), 5.92-5.90 (m, 1H), 5.19-5.09 (m, 1H), 4.43-4.38 (m, 1H), 3.98-3.63 (m, 4H), 2.76 (q, J=7.60Hz, 2H), 2.05- 1.86 (m, 2H), 1.21 (t, J=7.56Hz, 3H).
Embodiment 430:
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (2, 4- difluorophenyl) acetamide
Step 1:2- (2,4 difluorobenzene base) -2- hydroxyl acetamide
At 0 DEG C, to stirring of 2- (2,4- the difluorophenyl) -2- hydroxyacetic acid (1g, 5.21mmol) in methanol (50mL) Chloroacetic chloride (1.17mL, 15.63mmol) is added in solution.5h is stirred at room temperature in gained reaction mixture.The reaction is mixed Object is concentrated under reduced pressure.The crude material is dissolved in methanol (50mL) and ammonium hydroxide (7.24mL, 52.1mmol) is added.By the reaction 16h is stirred at room temperature in mixture.The reaction mixture is evaporated under reduced pressure, cold ethyl alcohol (15ml) is then added and stirs 5 points Clock.The mixture is filtered, 2- (2,4- difluorophenyl) -2- hydroxyl acetamide (800mg, 74.7% yield) is obtained, for ash White solid.LCMS (m/z)=188.04 [M+H]+.It is used without being further purified.
Step 2: methanesulfonic acid 2- amino -1- (2,4 difluorobenzene base) -2- oxoethyl ester
Under 0 DEG C of nitrogen, to 2- (2,4- difluorophenyl) -2- hydroxyl acetamide (0.800g, 3.89mmol) in dichloromethane Be added in agitating solution in alkane (20mL) triethylamine (3.39mL, 12.57mmol) and methane sulfonyl chloride (0.631mL, 6.28mmol).1h is stirred at room temperature in the reaction mixture.The reaction mixture down to ice cold water (15mL) and is used into dichloromethane Alkane (3X15mL) extraction.Combined organic layer is dried, filtered with anhydrous sodium sulfate, is then evaporated under reduced pressure.By the thick object Matter is ground with ether (3X 10mL), is filtered and is dried in vacuo, obtains methanesulfonic acid 2- amino -1- (2,4- difluorophenyl) -2- oxo Ethyl ester (1.3g, 84% yield), is pale solid.LCMS (m/z)=266.10 [M+H]+。
Step 3:2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulphur Base) -2- (2,4 difluorobenzene base) acetamide
To the chloro- 4- ethyl -6- of (S) -2- (3- hydroxyl pyrrolidine -1- base) pyridine -3,5- dimethoxy nitrile (in embodiment 418, Synthesis, 1.0g, 3.25mmol are described in step 1) thio second is added in the solution in n,N-Dimethylformamide (30mL) Sour potassium (0.379g, 3.25mmol).2h is stirred at room temperature in the mixture, then uses K2CO3(1.198g, 3.25mmol) and first Sulfonic acid 2- amino -1- (2,4- difluorophenyl) -2- oxoethyl ester (1.198g, 3.25mmol) processing.By the mixture in room Temperature stirring 16h.The reaction mixture is poured into ice cold water (100mL) and stirs 30min.Then it is used into DCM (3x 20mL) Extraction.Combined organic layer is washed with saline solution (20mL), is dried, filtered and is concentrated under reduced pressure with anhydrous sodium sulfate.It should Crude compound is ground with acetonitrile, obtains 2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine - 2- yl) sulfenyl) -2- (2,4- difluorophenyl) acetamide (0.485g, 33.3% yield) is pale solid.LCMS(m/z) =444.00 [M+H]+。1H NMR (400MHz, DMSO-d6): δ ppm 7.88 (s, 1H), 7.62-7.51 (m, 1H), 7.43 (s, 1H), 7.37-7.27 (m, 1H), 7.13 (t, J=8.55Hz, 1H), 5.83 (s, 1H), 5.16-5.09 (m, 1H), 4.43-4.35 (m, 1H), 3.94-3.58 (m, 4H), 2.76 (q, J=7.31Hz, 2H), 2.04-1.84 (m, 2H), 1.21 (t, J=7.56Hz, 3H)。
Embodiment 431
(R) -2- ((3,5- dicyano -4- ethyl -6- ((2- hydroxyethyl) (methyl) amino) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides
By 2- ((3,5- dicyano -4- ethyl -6- ((2- hydroxyethyl) (methyl) amino) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides (500mg describes synthesis in embodiment 147) are dissolved in the hot EtOH of 30mL and in Chiralpak AD-H, and 5 Positive HPLC chiral separation is carried out on micron column, uses 60:30 normal heptane: ethanol solvent system (no modifying agent).By the solvent It is removed under reduced pressure, obtains the second eluting peak of 230mg.2- ((3,5- dicyano -4- ethyl -6- ((2- hydroxyethyl) (methyl) ammonia Base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides.By VCD the and IR spectrum of the observation of the product and (R)-structure of simulation It calculates spectrum to be compared, absolute configuration is designated as (R)-.LCMS (m/z)=396.2 [M+H]+。1H NMR (400MHz, DMSO-d6) δ ppm 7.90 (s, 1H), 7.45-7.54 (m, 2H), 7.27-7.43 (m, 4H), 5.53 (s, 1H), 4.85 (t, J= 5.45Hz, 1H), 3.97-3.79 (m, 2H), 3.70-3.58 (m, 2H), 3.40 (s, 3H), 2.76 (q, J=7.52Hz, 2H), 1.21 (t, J=7.60Hz, 3H).
Embodiment 432
2- ((3,5- dicyano -6- (4- (cyclobutyl (methyl) amino) piperidin-1-yl) -4- ethylpyridine -2- base) sulphur Base) -2- (4- fluorophenyl) acetamide
Step 1:4- (cyclobutyl (methyl) amino) piperidines -1- t-butyl formate
In room temperature, by N- methyl ring butylamine (550mg, 6.46mmol) and 4- oxo-piperidine -1- t-butyl formate The mixture of (1287mg, 6.46mmol) stirring 20 minutes in methylene chloride (20mL).Then be added AcOH (0.037mL, 0.646mmol) and sodium cyanoborohydride (609mg, 9.69mmol).The mixture is stirred at room temperature 16 hours.By the reaction Mixture is quenched with water, and is allocated between methylene chloride 25mL and water 25mL.The organic phase is washed 3 times with water 10mL, uses sulphur Sour sodium is dry and is evaporated in vacuo, and obtains 4- (cyclobutyl (methyl) amino) piperidines -1- t-butyl formate (600mg), is colourless Oil.LCMS (m/z)=269.3 [M+H]+。
Step 2:N- cyclobutyl-N- methyl piperidine -4- amine
4- (cyclobutyl (methyl) amino) piperidines -1- t-butyl formate (580mg, 2.161mmol) is dissolved in methylene chloride In (15mL).It is added dropwise TFA (5mL, 64.9mmol).The mixture is stirred at room temperature overnight.Solvent in vacuo is removed, N- is obtained Cyclobutyl-N- methyl piperidine -4- amine (300mg).LCMS (m/z)=169.3 [M+H]+。
The chloro- 6- of step 3:2- (4- (cyclobutyl (methyl) amino) piperidin-1-yl) -4- ethylpyridine -3,5- dimethoxy nitrile
At 0 DEG C, by N- cyclobutyl-N- methyl piperidine -4- amine (150mg, 0.891mmol) and triethylamine (0.248mL, 1.783mmol) solution in DMF (10mL) be added dropwise to chloro- 4- ethylpyridine -3, the 5- dimethoxy nitrile of 2,6- bis- (in embodiment 3, Synthesis, 202mg, 0.891mmol are described in step 2) in the solution in DMF (10mL).The mixture is stirred at room temperature Overnight.The reaction mixture is quenched with water, is allocated between ethyl acetate 50mL and water 50mL.By organic phase water 25mL It is washed with saturated brine 25mL, with sodium sulphate drying and is evaporated in vacuo, obtains raw product, be brown oil.By raw product It adds to silicagel column (4g) and uses CH2Cl2/ MeOH (100/1) elution, obtains the chloro- 6- of 2- (4- (cyclobutyl (methyl) amino) piperidines- 1- yl) -4- ethylpyridine -3,5- dimethoxy nitrile (160mg).LCMS (m/z)=358.2 [M+H]+。
Step 4:2- ((3,5- dicyano -6- (4- (cyclobutyl (methyl) amino) piperidin-1-yl) -4- ethylpyridine -2- Base) sulfenyl) -2- (4- fluorophenyl) acetamide
By the chloro- 6- of 2- (4- (cyclobutyl (methyl) amino) piperidin-1-yl) -4- ethylpyridine -3,5- dimethoxy nitrile (160mg, 0.447mmol) and thioacetic acid potassium (51.1mg, 0.447mmol) are molten in n,N-Dimethylformamide (20mL) Liquid is stirred at room temperature 30 minutes.Then methanesulfonic acid 2- amino -1- (4- fluorophenyl) -2- oxoethyl ester is added (in embodiment 207, synthesis, 111mg, 0.447mmol are described in step 3) and triethylamine (0.125mL, 0.894mmol).By the mixture It is stirred at room temperature overnight.The reaction mixture is quenched with water, is allocated between ethyl acetate 50mL and water 50mL.This is organic It is mutually washed with water 25mL, saturated brine 25mL, with sodium sulphate drying and is evaporated in vacuo, obtains raw product, be brown oil.It will Raw product adds to silicagel column (12g) and uses CH2Cl2/ MeOH elution.The solvent in vacuo is evaporated, 2- ((3,5- dicyan are obtained Base -6- (4- (cyclobutyl (methyl) amino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- (4- fluorophenyl) acetamide (45mg) is Light brown solid.LCMS (m/z)=507.3 [M+H]+。1H NMR (400MHz, MeOD) δ 7.59 (dd, J= 8.4,5.3Hz, 2H), 7.17 (t, J=8.6Hz, 2H), 5.54 (s, 1H), 4.89-4.79 (m, 2H), 3.91-3.80 (m, 1H), 3.59-3.48 (m, 1H), 3.24 (dd, J=26.5,13.4Hz, 2H), 2.93 (q, J=7.5Hz, 2H), 2.62 (s, 3H), 2.41-2.20 (m, 4H), 2.13-2.01 (m, 2H), 1.97-1.76 (m, 4H), 1.32 (t, J=7.5Hz, 3H).
Compound (embodiment 441 to 696) in the following table 1 is generally prepared according to the above method, and is easy by this Field technical staff preparation.As used in following table and the whole instruction, the Stereocenter expression for indicating " or1 " is not known individually Other Stereocenter.
* embodiment 523 and 542 is considered as the 3:1 mixture of diastereoisomer, and wherein main component is as shown in the figure.
Embodiment 700:DNMT1 test-external
The compounds of this invention is measured to DNMT1 selective active in one or more following DNMT1 measurements, and can To be measured in one or more following DNMT3 measurements.
DNMT1 Breaklight test
Using the non-binding surface micropore plate (Corning 3575) of black, with 384 hole specification of standard with total volume for 50 μ l Carry out DNMT1 Breaklight external test.5 μ l people's overall length DNMT1 (inside generates) that ultimate density is 40nM are added to In 5 μ l substrate mixtures, the hemimethylation oligonucleotides which contains final concentration of 125nM (is synthesized in ATD Bio；5'- FAM-ATCTAGCG5ATCAGTTTTCTGATG5G5TAGAT-3 ', wherein 5=methyldeoxycytidine) and 2 μM of ultrapure SAM (Cisbio#62SAHZLD).Negative control hole uses 5 μ l DNMT1 and 5 μ l oligonucleotides but 0 μM of SAM.All reagents are 1 × measurement buffer (20mM Tris pH 6.8,25mM NaCl, 0.5mM MgCl2, 0.01%Triton X100 and 1mM DTT it is prepared in).Reaction is cultivated 45 minutes at 26 DEG C, 40 μ l detection reagents are then added and terminate reaction.The detection reagent is 1 × Gla measures buffer (20mM Tris pH 8.0,80mM NaCl, 0.75mM MgCl2, 0.01%Triton X100 and 1mM DTT), final concentration of 100 μM of SAH (Sigma#A9384) and 0.0008 unit/μ l Gla1 restriction endonuclease (Sibenzyme#E494) preparation in.After detection reagent is added, plate is protected from light and is cultivated 5 hours at room temperature.Then exist Fluorescence intensity, gain 400, integral are measured on PHERAstar FS (BMG Labtech) at Ex 485nm and Em 520nm Time is 100ms.
Gla1 Breaklight is against screening test
Gla1 Breaklight uses the non-binding surface micropore plate (Corning#3575) of black against screening test in vitro, With 384 hole specification of standard with 50 μ l of total volume progress.10 μ l substrate mixtures are added in instrument connection, containing final concentration of The hemimethylation oligonucleotides of 100nM (is synthesized in ATD Bio；5'-FAM-ATCTAGCG5ATCAGTTTTCTGATG5G5TAG AT-3 ' wherein 5=methyldeoxycytidine sequence) and the oligonucleotides of 25nM exhaustive methylation (synthesized in ATD Bio；5'-FAM- ATCTAG5G5ATCAGTTTTCTGATG5G5TAGAT-3 ' wherein 5=methyldeoxycytidine).Negative control hole uses 10 μ l 125nM hemimethylation oligonucleotides.Oligonucleotides measures buffer (20mM Tris pH 6.8,25mM NaCl, 0.5mM in 1x MgCl2, 0.01%Triton X100 and 1mM DTT) in prepare.40 μ l Gla1 detection reagents are added immediately, are surveyed in 1 × Gla Determine buffer (20mM Tris pH 8.0,80mM NaCl, 0.75mM MgCl2, 0.01%Triton X100 and 1mM DTT), Final concentration of 100 μM of SAH (Sigma#A9384) and 0.0008 unit/μ l Gla1 restriction endonuclease (Sibenzyme# E494 preparation in).After detection reagent is added, plate is protected from light and is cultivated 5 hours at room temperature.Then in PHERAstar FS (BMG Labtech fluorescence intensity, gain 400, time of integration 100ms are measured on) at Ex 485nm and Em 520nm.
DNMT3a/3l Breaklight test
External DNMT3a/3l Breaklight test uses the non-binding surface micropore plate (Corning#3575) of black, With 384 hole specification of standard with 50 μ l of total volume progress.The 5 μ l people DNMT3a/3l (inside generates) that ultimate density is 600nM are added Enter to 5 μ l and contains final concentration 125nM hemimethylation oligonucleotides (in ATD Bio synthesis；5'-FAM-ATCTAGCG5ATCAGTT TTCTGATG5G5TAGAT-3 ' wherein 5=methyldeoxycytidine) and the substrate of 2 μM of ultrapure SAM (Cisbio#62SAHZLD) it is mixed It closes in object.Negative control hole uses 5 μ l DNMT3a/31 and 5 μ l oligonucleotides, but also includes 200 μM of SAH.All reagents are equal In 1 × measurement buffer (20mM Tris pH 7.4,100mM NaCl, 1.5mM EDTA, 0.1mM MgCl2, 1mM CHAPS It is prepared in 1mM DTT).Reaction is cultivated 90 minutes at 37 DEG C, 40 μ l detection reagents are then added and terminate reaction.Detection examination Agent measures buffer (20mM Tris pH 8.0,80mM NaCl, 0.75mM MgCl in 1 × Gla2, 0.01%Triton X100 and 1mM DTT), final concentration of 200 μM of SAH (Sigma#A9384) and 0.0008 unit/μ l Gla1 restriction enzyme core Preparation in sour enzyme (Sibenzyme#E494).After detection reagent is added, plate is protected from light and is incubated 5 hours at room temperature.Then exist Fluorescence intensity, gain 400, integral are measured on PHERAstar FS (BMG Labtech) at Ex 485nm and Em 520nm Time is 100ms.
DNMT1 SPA test method:
Use the biochemical activity of SPA technology analysis DNMT1.Plate (Griener 784075) is covered into the hole 100nL/ in advance Compound (11 points, 3 times of serial dilutions).In the 2x enzymatic mixture that 5 μ L are added into the hole containing 5 μ L 2x substrate mixtures After start to react.Low control wells contain 5 μ L buffers rather than enzyme.Culture after forty minutes, is added 10 μ L and contains 1mM SAM The termination mix of (Sigma A7007) and 2mg/mL PEI pearl (Perkin Elmer RPNQ0098) reacts to terminate.By plate Sealing is centrifuged 1 minute, then emits optical filter/300s read access time using 613nm on Viewlux (Perkin Elmer) It is read after dark adaptation in >=30 minutes.Determination condition before being quenched include 40nM DNMT1 (601-1600, inside generate), 100nM 3H-SAM(American Radiolabeled Chemicals ART 0288)、900nM SAM(New England BioLabs B9003S) and 200nM hemimethylation DNA oligonucleotides (it is synthesized in Integrated DNA Technologies, 5 '-CCTCTTCTAACTGCCAT5GATCCTGATAGCAGGTGCATGC-3 '), in 50mM HEPES (pH 8.0), 2mM In MgCl2,1mM DTT, 0.01%NP-40 and 0.01%BSA.
Embodiment 701: external to the influence-of erythroid progenitor cells (EPC)
EPC was cultivated 5 days in the duplicate plate of the compound A containing serial dilution in 37 DEG C in 7th day.Then Analyze induction fetal hemoglobin (HbF, HbF ELISA) or the cell growth (Cell Titer-Glo) in hole).In two kinds of situations Under, signal standards is turned to the cell of intermedium control processing.Compound A induces HbF to increase, average pEC50=6.5, and 50% cell is inhibited to grow, average pGI50=5.9.The representative curve of every kind of measurement is shown in figure 1A.
In order to measure influence of the compound A to DNA methylation, harvest handles 3 days EPC with compound A, and to gene Group DNA carries out bisulfite sequencing.Select 9 sites CpG in the promoter region of HBG1 and HBG2 locus or neighbouring Methylation, and based on they as during RBC acceptor garland rate DNMT1 methylate site before characterization analyzed (Mabaera etc., Blood:110 (4).2007).As shown in Figure 1B, compared with the cell of medium processing, all 9 sites are equal Display methylation is reduced, and averagely reduces 65 ± 5%.
Method
7th day erythroid progenitor cells (EPC) culture, amplification and characterization
All donors both provide the Written informed consent using its sample, and the collection and use of sample have obtained machine The approval of structure examination board.The people's bone marrow CD34+ cell of all freezen protectives used herein is all obtained from AllCells (Emeryville, CA), and usually from different donors.In the 7th day culture CD34+ cell to generate EPC.In short, It is being supplemented with 2mM L-Glutamine, 40 μ g/mL human ldls (StemCell Technologies), 10ng/mL weight Group people's (rh) interleukins IL-3 (R&D Systems, Minneapolis, MN), 100ng/mL rh stem cell factor (R&D Systems it) is trained with the H3000Stemspan of 0.5U/mL hematopoietin (Invitrogen, Grand Island, NY) It supports in base (StemCell Technologies Vancouver, BC, Canada), is trained in 5%CO2,5%O2 at 37 DEG C Support 1,000,000 cells.It is separated on day 4 with above-mentioned complete medium and cultivates cell again, and in the 7th day harvest cell to comment Estimate the expression of Tagged-RBC object and assessment gamma globulin induction.Then by the 7th day EPC in the 95% tire ox containing 5%DMSO Serum (FBS；Invitrogen it is frozen in liquid nitrogen in) with 5 to 1,000 ten thousand cells/mL, for subsequent use.
In compound processing, the 7th day EPC of the freezing prepared as described above is thawed, washed once and weigh as described above It is suspended from complete medium, in addition to rhEPO increases to 3U/mL.It counts cell and is diluted to 3.3 × 103Cell/mL with bed board extremely In assay plate.Then Multidrop is usedTMCombi reagent distributor (Thermo Scientific) distributes cell with 30 holes μ L/ Into 384 porocyte culture plates, wherein test compound is with the predistribution of the hole 100nL/.Black transparent bottom plate (Greiner Bio- One；And blank (Greiner Bio-One 781090)；781080) it is respectively used to ELISA and Cell Titer-Glo measurement.It surveys Final cell density in fixed is 1,000, every hole cell, for 22 serial dilutions, final compound concentration 33nM (most It is high) and 6.6nM (minimum) between.
In order to monitor cell health and cell growth, using Cell Titer-Glo (being explained in detail below) in plating cells (the 0th day) progress cell growth measurement.For compound processing, tissue culture plate is used into 5%CO at 37 DEG C2Culture 5 days.
Fetal hemoglobin (HbF) ELISA
By coated anti-HbF Ab (Bethyl Lab；Catalog number (Cat.No.) A80-136A) in coating buffer (0.05M carbonate- Bicarbonate, pH9.6) in dilution 100 times, be then added to (Thermo in 384 hole MaxiSorp elisa plates with 20 holes μ L/ Fisher；Catalog number (Cat.No.) 464718).After cultivating 1 hour at room temperature, with ELISA washing buffer (50mM Tris, 0.05% Tween 20, pH8.0) use EL406 board cleaning machine (BioTek, Winooski, VT) washing plate twice.Then, by 40 holes μ L/ by The Block buffer of 50mM Tris and 1%BSA (pH8.0) composition is added in plate, and is saved overnight at 4 DEG C with cover board, or straight To minute.Coated elisa plate is stable for up to 30 days at 4 DEG C.On the day of measurement, washed with ELISA washing buffer It washs plate twice, cell lysate is then added.
At 37 DEG C, 5%CO2After lower 5 days, the tissue culture plate for being used for ELISA measurement is put at least 2 in -80 DEG C of refrigerators Hour.After thawing at room temperature, 30 μ L cell lysis buffer solution (Invitrogen are added into each hole；Catalog number (Cat.No.) FNN0011 is supplemented with 1x protease inhibitors), and obtained cell lysate is moved with Cybi-Well (Jena, Germany) Liquid device mixes 8 times.After the mixing operation, the lysate in 20 holes μ L/ is transferred to above-mentioned coated elisa plate, then in room Temperature lower culture 1 hour.ELISA assay plate is washed three times with ELISA washing buffer.Then the 1:75,000 of every 20 μ L of hole is added Anti- HbF Ab (the Bethyl Labs of analyte detection is conjugated to 100,000 diluted horseradish peroxidases (HRP)；Catalog number (Cat.No.) A80- 136P, dilution, 1%BSA, 0.05% Tween-20 in 50mM Tris [pH 8.0]).It, will after being further cultured for 1 hour at room temperature Plate washs four times, and tetramethyl benzidine ELISA substrate (the Thermo Scientific in 20 holes μ L/ is then added；Catalog number (Cat.No.) 34028).After being protected from light culture at room temperature 3-10 minutes, the stop bath (0.2M sulfuric acid) in 20 holes μ L/ is added.Then it uses EnVision plate reader (PerkinElmer, Waltham, MA) read plate at 450nm absorbance (OD450).Only containing DMSO's The average reading of control wells (16 holes in the 6th column of each assay plate) is used as standardized foundation level.By every kind of chemical combination Horizontal percentage (100%) based on the gamma globulin level calculation in the hole of object processing.
Calculating instrument is counted using the customization based on R (R Foundation for Statistical Computing) The normalized response for 22 kinds of concentration for testing compound to every kind carries out curve fitting.From the matched curve of every kind of reactive compound Determine EC50 value (compound concentration 1/2Max%) and corresponding Max%.
Cell growth analysis in 7th day EPC
At 37 DEG C, 5%CO2After culture 5 days, cell growth measurement is carried out on tissue culture plate.By every 15 μ L's of hole Cell Titer-Glo (Promega, Madison, WI) measures reagent and is added in assay plate.Then plate is cultivated 10 at room temperature Minute, then read on ViewLux1430 (Perkin Elmer) using illumination scheme.Only the control wells containing DMSO are (every A assay plate the 6th column in 16 holes) average reading be used as standardized foundation level.The Cell of each instrument connection Titer-Glo signal is calculated as the percentage (100%) of foundation level.Using based on R (R Foundation for Statistical Computing) customization statistics calculating instrument to every kind test compound 22 kinds of concentration normalization ring It should carry out curve fitting.
In order to monitor cell health and cell growth, the Cell Titer-Glo signal of DMSO control wells was obtained with the 0th day The signal obtained is compared and (sees above).The cell of health is grown, was usually observed at the 5th day relative to the 0th -day-old About 20 times of increase.
The analysis of bisulfites sequence
Using ZYMO gDNA kit (Zymo Research, Irvine, CA), in the presence of compound, from 37 DEG C, it is cultivated in the 7th day EPC under 5%CO2 and 5%O2, extracts genomic DNA in duplicate.Isolated DNA uses Zymo EZ DNA methylation kit carries out bisulfite conversion.Using ABIMethyl Primer Express software design HBG1 and The primer sets in bisulf iotate-treated region are used in HBG2.Analyzed area includes 9 previously described DNMT1 dependent DNAs Methylation sites (Mabaera etc., Blood:110 (4).2007).It further DNA amplification and is used on fluidigm Agilent biological analyser carries out QC'd.Carry out MiSeq using Illumina system, and using ArrayStudio v8 and CLC-GWB v8.1 analysis output.
Embodiment 702:MV-4-11 antiproliferative activity (pEC50Classification)
Cell Proliferation tests by checking that the growth of wide scope inoculum density allows maximum to identify in 384 hole formats With the condition for continuing to multiply 6 days, the optimum cell inoculum density of empirically determined MV-4-11AML cell.With 20 points 2 times 24 hours before dilution series compound or 0.15%DMSO processing, by MV-4-11 plating cells in duplicate plate.It will Plate is at 37 DEG C, 5%CO2Middle culture 6 days.Then CellTiter-Glo (CTG) (Promega) lytic cell is used, with suitable enzyme It marks instrument and detects chemiluminescence signal.In addition, compound (T is added0) when harvest untreated cell plates with quantitative initial cell Density.The CTG value that processing obtains after 6 days is expressed as T0The percentage of value, and map relative to compound concentration.With four parameter sides Journey fitting data calculates growth IC to generate concentration-response curve, from the curve50Value.
Embodiment 703: sickle cell's measurement-is in vivo
The in vivo efficacy of compound A is measured using the mouse model of drepanocytosis, the compound A was previously shown It is external with strength in the primary erythroid progenitor cells of people for being originated from normal bone marrow or sickle cell patients peripheral blood mononuclear cells Activity.
Method
Preparatory work of experiment
According to the U.S./british animal nursing standard, the activity in vivo of compound A is studied in sickle cell's mouse model.
When studying beginning, male and female human hemoglobin transgenic mice [B6；129-Hbatm1(HBA)Tow/ Hbbtm2 (HBG1, HBB*) Tow/J mouse (Jackson Laboratories, ME)] about 6-8 week old, weigh about 15-25 grams. Within the bounds of possibility, group is that gender is balanced and is made of 6 mouse.
Experimental program
Within two weeks time, mouse medium (10%DMA/ is given with (BID) twice daily by oral route 90%PEG400), 10 or 50mg/kg compound A, on every Fridays day.
At the end of the administration phase, mouse is set to be euthanized by CO2 asphyxia, and will arrive from venacaval blood collection It is analyzed in EDTA pipe for fetal hemoglobin.By high effective liquid chromatography for measuring %HbF albumen, and pass through flow cytometry Measure %F cell (red blood cell of expression HbF).It is conjugated with APC (Life Technologies, Grand Island, NY) small The anti-human HbF antibody of murine monoclonal is used to identify the erythroid cells of expression HbF.Nucleus dyestuff syto16 (Life Technologies) for separating granulophilocyte and RBC groups.Protein and cell data are analyzed in Bio-Rad D10 respectively It is collected on instrument (Bio-Rad, Benicia, CA) and FACs Canto I (BD BioSciences, San Jose, CA).With Flowjo v7 software (Treestar, Inc Ashland.OR) analyzes flow cytometry data.Measure control group and treatment group Cell mean and standard deviation.By map data and use the single factor test ANOVA (Graphpad with Tukey post-hoc tests Prism v5 [La Jolla, CA]) it is analyzed.
As a result
Compound A causes agent with 10 or 50mg/kg oral administration, daily BID (administration 5 days is discontinued 2 days, is administered 4 days) The increase of the %HbF albumen of amount dependence and significance,statistical (respectively 5.4 times, p < 0.05；10.3 times, p < 0.001) [figure 2A]。
After 10 or 50mg/kg BID is administered orally during 2 weekly doses, compound A processing leads to %F granulophilocyte Increase with %F RBC.Observe %F granulophilocyte (respectively 4 times and 9 times；P < 0.001) and (respectively 6 times of %F RBC With 8 times；P < 0.001) dose dependent and significance,statistical increase [Fig. 2 B].
Embodiment 704:- capsule composition
It is prepared for applying peroral dosage form of the invention by filling the two panels hard gelatin capsule of standard, wherein described The ratio of ingredient is as shown in table 2 below.
Table 2
The parenteral composition of embodiment 705:- injectable
By the 2- ((3,5- dicyano -4- ethyl-for stirring 1.7 weight % in the aqueous solution of propylene glycol of 10 volume % 6- (1,7- diaza spiro [3.5] nonyl- 1- yl) pyridine -2- base) sulfenyl) -2- phenyl-acetamides trifluoroacetate (embodiment 38 Compound) to prepare injectable forms of the invention are administered.
Embodiment 706: tablet composition
By sucrose as shown in Table 3 below, calcium sulfate dihydrate and DNMT1 the activity inhibitor ratio shown in 10% gelatin solution is mixed and is pelletized.Wet granular is sieved, it is dry, it is mixed with starch, talcum and stearic acid；It is sieved and is pressed into Tablet.
Table 3
Bioactivity
Those skilled in the art will appreciate that said determination is influenced by experimental variability.It will be understood, therefore, that below The value provided is merely exemplary.
Generally, according to above-mentioned Breaklight measuring method and/or SPA measuring method test the compounds of this invention to DNMT1 Activity.
DNMT1 tables of data:
Hierarchical categories (pXC50):
A class: < 4.5
B class: 4.5≤x < 6.0
C class: 6.0≤x < 6.5
D class: >=6.5
Comment:
1. compound is classified activity shown in showing in above-mentioned Breaklight or SPA measurement.
2. wherein space is empty, then the compound does not measure in the test.
Generally, according to above-mentioned DNMT1 Breaklight measuring method testing example 1-67 compound and in repetition Experimental implementation in show relative to DNMT1 average IC50mcM value be 0.12-4.78.
Generally, according to above-mentioned DNMT1 Breaklight measuring method testing example 5,12,20,25,28,37,40, 43,56 and 61 compound and show that the average IC50mcM value relative to DNMT1 is in duplicate experimental implementation 0.50。
Generally, according to above-mentioned DNMT1 Breaklight measuring method testing example 10,13,26,30,32,33,34, 49,55 and 59 compounds and show that the average IC50mcM value relative to DNMT1 is > 0.50 in duplicate experimental implementation < 0.75.
Generally, according to above-mentioned DNMT1 Breaklight measuring method testing example 8,9,21,22,35,36,38, 41,58 and 63 compounds and show that the average IC50mcM value relative to DNMT1 is > 0.75 in duplicate experimental implementation.
Generally, according to above-mentioned DNMT1 Breaklight measuring method and/or SPA measuring method testing example 68-149 Compound and shown in duplicate experimental implementation relative to DNMT1 average pIC50 value be 4.8-7.3.
Generally, according to above-mentioned DNMT1 Breaklight measuring method and/or SPA measuring method testing example 69,72, 74,78,81,92,102,103,108,109,129,133,216,247,266,279,310,377,531,540 and 617 chemical combination Object and shown in duplicate experimental implementation relative to DNMT1 average pIC50 value be 6.0.
Generally, according to above-mentioned DNMT1 Breaklight measuring method and/or SPA measuring method testing example 70,82, 85、99、110、117、119、120、126、130、131、132、165、237、283、286、303、324、379、496、546、 602,683 and 685 compound and shown in duplicate experimental implementation the average pIC50 value relative to DNMT1 be > 6.0 and≤6.5.
Generally, according to above-mentioned DNMT1 Breaklight measuring method and/or SPA measuring method testing example 76,77, 80、83、86、115、121、122、125、136、137、138、143、148、149、168、409、425、477、523、562、592、 626 and 649 compound and show that the average pIC50 value relative to DNMT1 is > 6.5 in duplicate experimental implementation.
Generally, according to above-mentioned 15 compound of DNMT1 Breaklight measuring method testing example and duplicate Show that the average IC50mcM value relative to DNMT1 is 0.44 in experimental implementation.
Generally, according to above-mentioned 11 compound of DNMT1 Breaklight measuring method testing example and duplicate Show that the average IC50mcM value relative to DNMT1 is 0.58 in experimental implementation.
Generally, according to above-mentioned 48 compound of DNMT1 Breaklight measuring method testing example and duplicate Show that the average IC50mcM value relative to DNMT1 is 0.89 in experimental implementation.
Generally, according to 72 chemical combination of above-mentioned DNMT1 Breaklight measuring method and/or SPA measuring method testing example Object and shown in duplicate experimental implementation relative to DNMT1 average pIC50 value be 5.7.
Generally, according to 79 chemical combination of above-mentioned DNMT1 Breaklight measuring method and/or SPA measuring method testing example Object and shown in duplicate experimental implementation relative to DNMT1 average pIC50 value be 6.5.
Generally, according to 86 chemical combination of above-mentioned DNMT1 Breaklight measuring method and/or SPA measuring method testing example Object and shown in duplicate experimental implementation relative to DNMT1 average pIC50 value be 6.7.
Generally, according to the change of above-mentioned DNMT1 Breaklight measuring method and/or SPA measuring method testing example 115 It closes object and shows that the average pIC50 value relative to DNMT1 is 6.7 in duplicate experimental implementation.
Generally, according to the change of above-mentioned DNMT1 Breaklight measuring method and/or SPA measuring method testing example 119 It closes object and shows that the average pIC50 value relative to DNMT1 is 6.4 in duplicate experimental implementation.
Generally, according to the change of above-mentioned DNMT1 Breaklight measuring method and/or SPA measuring method testing example 138 It closes object and shows that the average pIC50 value relative to DNMT1 is 7.0 in duplicate experimental implementation.
Generally, according to the change of above-mentioned DNMT1 Breaklight measuring method and/or SPA measuring method testing example 337 It closes object and shows that the average pIC50 value relative to DNMT1 is 5.5 in duplicate experimental implementation.
Generally, according to the change of above-mentioned DNMT1 Breaklight measuring method and/or SPA measuring method testing example 540 It closes object and shows that the average pIC50 value relative to DNMT1 is 5.5 in duplicate experimental implementation.
Generally, according to the change of above-mentioned DNMT1 Breaklight measuring method and/or SPA measuring method testing example 617 It closes object and shows that the average pIC50 value relative to DNMT1 is 5.6 in duplicate experimental implementation.
Generally, according to the change of above-mentioned DNMT1 Breaklight measuring method and/or SPA measuring method testing example 266 It closes object and shows that the average pIC50 value relative to DNMT1 is 5.7 in duplicate experimental implementation.
Generally, according to the change of above-mentioned DNMT1 Breaklight measuring method and/or SPA measuring method testing example 310 It closes object and shows that the average pIC50 value relative to DNMT1 is 5.7 in duplicate experimental implementation.
Generally, according to the change of above-mentioned DNMT1 Breaklight measuring method and/or SPA measuring method testing example 216 It closes object and shows that the average pIC50 value relative to DNMT1 is 5.8 in duplicate experimental implementation.
Generally, according to the change of above-mentioned DNMT1 Breaklight measuring method and/or SPA measuring method testing example 247 It closes object and shows that the average pIC50 value relative to DNMT1 is 5.8 in duplicate experimental implementation.
Generally, according to the change of above-mentioned DNMT1 Breaklight measuring method and/or SPA measuring method testing example 531 It closes object and shows that the average pIC50 value relative to DNMT1 is 5.8 in duplicate experimental implementation.
Generally, according to the change of above-mentioned DNMT1 Breaklight measuring method and/or SPA measuring method testing example 279 It closes object and shows that the average pIC50 value relative to DNMT1 is 6 in duplicate experimental implementation.
Generally, according to the change of above-mentioned DNMT1 Breaklight measuring method and/or SPA measuring method testing example 379 It closes object and shows that the average pIC50 value relative to DNMT1 is 6.1 in duplicate experimental implementation.
Generally, according to the change of above-mentioned DNMT1 Breaklight measuring method and/or SPA measuring method testing example 165 It closes object and shows that the average pIC50 value relative to DNMT1 is 6.2 in duplicate experimental implementation.
Generally, according to the change of above-mentioned DNMT1 Breaklight measuring method and/or SPA measuring method testing example 283 It closes object and shows that the average pIC50 value relative to DNMT1 is 6.2 in duplicate experimental implementation.
Generally, according to the change of above-mentioned DNMT1 Breaklight measuring method and/or SPA measuring method testing example 303 It closes object and shows that the average pIC50 value relative to DNMT1 is 6.2 in duplicate experimental implementation.
Generally, according to the change of above-mentioned DNMT1 Breaklight measuring method and/or SPA measuring method testing example 324 It closes object and shows that the average pIC50 value relative to DNMT1 is 6.2 in duplicate experimental implementation.
Generally, according to the change of above-mentioned DNMT1 Breaklight measuring method and/or SPA measuring method testing example 602 It closes object and shows that the average pIC50 value relative to DNMT1 is 6.3 in duplicate experimental implementation.
Generally, according to the change of above-mentioned DNMT1 Breaklight measuring method and/or SPA measuring method testing example 237 It closes object and shows that the average pIC50 value relative to DNMT1 is 6.4 in duplicate experimental implementation.
Generally, according to the change of above-mentioned DNMT1 Breaklight measuring method and/or SPA measuring method testing example 496 It closes object and shows that the average pIC50 value relative to DNMT1 is 6.4 in duplicate experimental implementation.
Generally, according to the change of above-mentioned DNMT1 Breaklight measuring method and/or SPA measuring method testing example 546 It closes object and shows that the average pIC50 value relative to DNMT1 is 6.4 in duplicate experimental implementation.
Generally, according to the change of above-mentioned DNMT1 Breaklight measuring method and/or SPA measuring method testing example 286 It closes object and shows that the average pIC50 value relative to DNMT1 is 6.5 in duplicate experimental implementation.
Generally, according to the change of above-mentioned DNMT1 Breaklight measuring method and/or SPA measuring method testing example 683 It closes object and shows that the average pIC50 value relative to DNMT1 is 6.5 in duplicate experimental implementation.
Generally, according to the change of above-mentioned DNMT1 Breaklight measuring method and/or SPA measuring method testing example 685 It closes object and shows that the average pIC50 value relative to DNMT1 is 6.5 in duplicate experimental implementation.
Generally, according to the change of above-mentioned DNMT1 Breaklight measuring method and/or SPA measuring method testing example 626 It closes object and shows that the average pIC50 value relative to DNMT1 is 6.7 in duplicate experimental implementation.
Generally, according to the change of above-mentioned DNMT1 Breaklight measuring method and/or SPA measuring method testing example 168 It closes object and shows that the average pIC50 value relative to DNMT1 is 6.7 in duplicate experimental implementation.
Generally, according to the change of above-mentioned DNMT1 Breaklight measuring method and/or SPA measuring method testing example 409 It closes object and shows that the average pIC50 value relative to DNMT1 is 6.8 in duplicate experimental implementation.
Generally, according to the change of above-mentioned DNMT1 Breaklight measuring method and/or SPA measuring method testing example 592 It closes object and shows that the average pIC50 value relative to DNMT1 is 6.8 in duplicate experimental implementation.
Generally, according to the change of above-mentioned DNMT1 Breaklight measuring method and/or SPA measuring method testing example 425 It closes object and shows that the average pIC50 value relative to DNMT1 is 6.8 in duplicate experimental implementation.
Generally, according to the change of above-mentioned DNMT1 Breaklight measuring method and/or SPA measuring method testing example 649 It closes object and shows that the average pIC50 value relative to DNMT1 is 6.9 in duplicate experimental implementation.
Generally, according to the change of above-mentioned DNMT1 Breaklight measuring method and/or SPA measuring method testing example 477 It closes object and shows that the average pIC50 value relative to DNMT1 is 7 in duplicate experimental implementation.
Generally, according to the change of above-mentioned DNMT1 Breaklight measuring method and/or SPA measuring method testing example 523 It closes object and shows that the average pIC50 value relative to DNMT1 is 7.1 in duplicate experimental implementation.
Generally, according to the change of above-mentioned DNMT1 Breaklight measuring method and/or SPA measuring method testing example 562 It closes object and shows that the average pIC50 value relative to DNMT1 is 7.1 in duplicate experimental implementation.
Generally, according to above-mentioned DNMT3A and DNMT3B Breaklight measuring method testing example 3,6,7,8,9, 35,41,47,52 and 56 compound, and show that average IC50mcM value is greater than 500mcM in duplicate experimental implementation.
Although by the way that explained above is the preferred embodiment of the present invention, it should be appreciated that, the present invention is not limited to public here The accurate explanation opened, and retain the right of all modifications fallen within the scope of the appended claims.

Claims (40)

1. the method that treatment is selected from following disease in the mammal for having this to need: syndrome, β hemoglobin before cancer, cancer Disease, drepanocytosis, sickle-cell anemia and beta Thalassemia comprising to the mammal dosage treatment effective amount Formula (Ibr) compound:
Wherein:
X1brAnd X2brIndependently selected from:
Hydrogen,
- CN,
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
Re,
-OC1-6Alkyl,
-ORe,
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl,
By RdReplace 1-4 Heterocyclylalkyl,
- SH, and
-SRa；
YbrIt is selected from: S, NH, NRz, O, S (O) and S (O)2；
R1brIt is selected from:
-NH2,
-NHRa,
-NRbRc,
- CN,
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
Re,
-OC1-6Alkyl,
-ORe,
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl,
By RdReplace 1-4 Heterocyclylalkyl,
Aryl,
By RdReplace 1-4 aryl,
Heteroaryl,
By RdReplace 1-4 heteroaryl,
- SH, and
-SRa；
R3brIt is selected from:
Hydrogen,
C1-6Alkyl,
Re,
Heterocyclylalkyl,
By RdReplace 1-4 Heterocyclylalkyl,
Aryl,
By RdReplace 1-4 aryl,
Heteroaryl, and
By RdReplace 1-4 heteroaryl；With
R5brIt is selected from:
-NH2,
-NHRa,
-NRbRc,
Aryl,
By RdReplace 1-4 aryl,
-C1-6Alkyl,
-OC1-6Alkyl,
-ORe,
- O aryl,
By RdReplace 1-4-O aryl,
- O heteroaryl,
By RdReplace 1-4-O heteroaryl,
- SH, and
-SRa；
Wherein:
Each RaIndependently selected from
C1-6Alkyl,
Re,
Aryl,
By RdReplace 1-4 aryl,
Heteroaryl,
By RdReplace 1-4 heteroaryl,
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl, and
By RdReplace 1-4 Heterocyclylalkyl；
RbAnd RcIndependently selected from:
C1-6Alkyl,
Re,
Aryl,
By RdReplace 1-4 aryl,
Heteroaryl,
By RdReplace 1-4 heteroaryl；
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl, and
By RdReplace 1-4 Heterocyclylalkyl, or
RbAnd RcNitrogen connected to them and optionally 1 to the 3 additional hetero atom independently selected from O, N and S are formed together Heterocyclylalkyl,
It is optionally replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
Re,
-ORe,
Aryl,
By RdReplace 1-4 aryl,
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl, and
By RdReplace 1-4 Heterocyclylalkyl,
C1-4Alkoxy,
- CN,
Oxo,
- OH,
- COOH,
-NO2,
-NH2,
-N(H)C1-5Alkyl,
-N(H)Re,
-N(C1-5Alkyl)2,
-NReRe,
-N(Re)C1-5Alkyl,
-ONHC(NH)NH2,
- O Heterocyclylalkyl,
- NH naphthenic base,
-N(C1-5Alkyl) naphthenic base,
- NH Heterocyclylalkyl,
-N(C1-5Alkyl) Heterocyclylalkyl,
-S(O)2C1-4Alkyl,
-SO2NH2
-S(O)2Phenyl,
Benzoyl,
2- methylcyclopropyl groups,
Imidazole radicals,
(methoxypyridylmethyl) amino,
(methylcyclopropylmethyl) amino,
(fluorophenyl methyl) amino,
(methy oxetane ylmethyl) amino, and
(methyl-cyclobutyl methyl) amino；
Each RdIndependently selected from:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
Re,
Heteroaryl,
By RxReplace 1-4 heteroaryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 substitutions independently selected from the following The C that base replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Naphthenic base,
By RxReplace 1-4 naphthenic base,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 substitutions independently selected from the following The C that base replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Heterocyclylalkyl,
By RxReplace 1-4 Heterocyclylalkyl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 substitutions independently selected from the following The C that base replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Aryl,
By RxReplace 1-4 aryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 substitutions independently selected from the following The C that base replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
C1-4Alkoxy,
Replaced 1-4 C by fluorine1-4Alkoxy,
- O aryl,
By RxReplace 1-4-O aryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 substitutions independently selected from the following The C that base replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-ORe,
- C (O) H,
-C(O)Rzz,
- C (O) aryl,
By RzzReplace 1-4 times-C (O) aryl,
- C (O) heteroaryl,
By RzzReplace 1-4 times-C (O) heteroaryl,
- OC (O) H,
-CO(O)Rzz,
- OC (O) aryl,
By RzzReplace 1-4 times-CO (O) aryl,
- OC (O) heteroaryl,
By RzzReplace 1-4 times-OC (O) heteroaryl,
- SH,
-SRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 substitutions independently selected from the following The C that base replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- S (O) H,
-S(O)Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 substitutions independently selected from the following The C that base replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2H,
-S(O)2Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 substitutions independently selected from the following The C that base replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2NH2,
-S(O)2NHRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 substitutions independently selected from the following The C that base replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from:
Aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl, and replaced by 1-6 substituent groups independently selected from the following C1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-P(O)(CH3)2,
-NHS(O)2H,
-NHS(O)2Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 substitutions independently selected from the following The C that base replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- NHC (O) H,
-NHC(O)Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 substitutions independently selected from the following The C that base replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-C(O)NH2,
-C(O)NHRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 substitutions independently selected from the following The C that base replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-C(O)NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl, and it is independent by 1-6 The C that ground substituent group selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- C (O) OH,
-C(O)ORx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 substitutions independently selected from the following The C that base replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Oxo,
- OH,
-NH2,
-NHRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 substitutions independently selected from the following The C that base replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl, and it is independent by 1-6 The C that ground substituent group selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-NH2,
- CN,
-NHC(O)NH2,
-NHC(O)NHRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 substitutions independently selected from the following The C that base replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-NHC(O)NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl, and it is independent by 1-6 The C that ground substituent group selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Each ReIndependently selected from:
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Fluorine,
Chlorine,
Bromine,
Iodine,
-OC1-6Alkyl,
- the OC replaced by 1-6 substituent groups independently selected from the following1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-OC(O)C1-6Alkyl,
- OC (O) C replaced by 1-6 substituent groups independently selected from the following1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With- CN,
-ONHC(NH)NH2,
-OP(O)(OH)2,
- SH,
-SRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 substitutions independently selected from the following The C that base replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- S (O) H,
-S(O)Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 substitutions independently selected from the following The C that base replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2H,
-S(O)2Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 substitutions independently selected from the following The C that base replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Oxo,
- OH,
-NH2,
-NHRxx,
Wherein RxxSelected from aryl, heteroaryl, naphthenic base, by C1-4Naphthenic base that alkoxy replaces, by 1-6 independently selected from Under substituent group replace C1-4Alkoxy: fluorine, triazolyl, cyclopropyl, oxo ,-ORxy,-COOH ,-CN and-NRxyRxz, wherein RxyAnd RxzIndependently selected from:
Hydrogen, aryl, C1-5Alkyl cycloheteroalkyl, C1-6Alkyl and the C replaced by 1-6 substituent groups independently selected from the following1-6Alkane Base: fluorine, oxo ,-ORxy,-COOH ,-CN and-NRxyRxz, wherein RxyAnd RxzIndependently selected from: hydrogen, aryl, C1-5Alkyl and by The C that 1-4 substituent groups independently selected from the following replace1-5Alkyl: fluorine, triazolyl, cyclopropyl, oxo ,-OH ,-OC1-5Alkyl, Replaced 1-6-OC by fluorine and-COOH1-5Alkyl,
-NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-4Alkoxy, C1-6Alkyl and by The C that 1-6 substituent groups independently selected from the following replace1-6Alkyl: fluorine, C1-4Alkoxy, triazolyl, cyclopropyl, oxo ,- OH、-COOH、-NH2With-CN,
Guanidine radicals,
- C (O) OH,
-C(O)ORx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 substitutions independently selected from the following The C that base replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-C(O)NH2,
-C(O)NHRx,
Wherein RxSelected from aryl, heteroaryl ,-OH, C1-4Alkoxy, naphthenic base, by HO- (C1-4Alkyl)-the naphthenic base, miscellaneous that replaces Naphthenic base, by HO- (C1-4Alkyl)-replace Heterocyclylalkyl, C1-6It alkyl and is taken by 1-6 substituent groups independently selected from the following The C in generation1-6Alkyl: fluorine, oxo ,-OH ,-COOH, heteroaryl ,-NH2With-CN,
-C(O)NRx1Rx2,
Wherein Rx1And Rx2Be each independently selected from aryl, heteroaryl, naphthenic base, by HO- (C1-4Alkyl)-the naphthenic base, miscellaneous that replaces Naphthenic base, C1-6Alkyl and the C replaced by 1-6 substituent groups independently selected from the following1-6Alkyl: fluorine, oxo ,-OH ,- COOH、-NH2With-CN,
Or Rx1And Rx2The nitrogen connected to them and optionally 1-3 additional hetero atoms for being independently selected from O, N and S are formed together Heterocyclylalkyl is optionally replaced by 1-5 substituent groups independently selected from the following: fluorine, oxo ,-OH, HO- (C1-4Alkyl)-,- COOH、-NH2With-CN,
Aryl,
By RxReplace 1-4 aryl,
Wherein RxSelected from fluorine, chlorine, bromine, iodine, aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6It alkyl and is independently selected by 1-6 The C replaced from substituent group below1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2、-N(CH3)2、-NHC(O)C1-4Alkyl and- CN,
- O aryl,
By RxReplace 1-4-O aryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 substitutions independently selected from the following The C that base replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2、-N(CH3)2With-CN,
Heteroaryl,
By RxReplace 1-4 heteroaryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-4Alkoxy, C1-6Alkyl and by 1-6 independently selected from The C that substituent group below replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- O heteroaryl,
By RxReplace 1-4-O heteroaryl,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 substitutions independently selected from the following The C that base replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2、-N(CH3)2With-CN,
Naphthenic base,
By RxReplace 1-4 naphthenic base,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 substitutions independently selected from the following The C that base replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2、-N(CH3)2With-CN,
Heterocyclylalkyl,
By RxReplace 1-4 Heterocyclylalkyl,
Wherein RxSelected from oxo ,-OH ,-N (C1-4Alkyl)2, aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 The C that a substituent group independently selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2、-N(CH3)2With-CN,
-S(O)2NH2,
-S(O)2NHRx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 substitutions independently selected from the following The C that base replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-S(O)2NRx1Rx2,
Wherein Rx1And Rx2It is each independently selected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and independent by 1-6 The C that ground substituent group selected from the following replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-NHS(O)2H,
-NHS(O)2Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 substitutions independently selected from the following The C that base replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-OC(O)NH2,
-NHC(O)Rx,
Wherein RxSelected from aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, C1-6Alkyl and by 1-6 substitutions independently selected from the following The C that base replaces1-6Alkyl: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
-NHC(O)NHRxp,
Wherein RxpSelected from heteroaryl, naphthenic base, Heterocyclylalkyl and the C replaced by 1-4 substituent groups independently selected from the following1-6 Alkyl :-COOH ,-NH2With-CN,
-NHC(O)NRx3Rx4,
Wherein Rx3And Rx4It is each independently selected from heteroaryl, naphthenic base, Heterocyclylalkyl and is taken by 1-6 is independently selected from the following The C replaced for base1-6Alkyl :-COOH ,-NH2With-CN,
-NHC(O)C(O)NH2,
-NO2With
-CN；With
RzIt is selected from
C1-6Alkyl,
Re,
Naphthenic base,
By RdReplace 1-4 naphthenic base,
Heterocyclylalkyl, and
By RdReplace 1-4 Heterocyclylalkyl；
RzzIt is selected from
C1-6Alkyl, and
Re；
On condition that:
X1brAnd X2brIt is not all hydrogen；
Or its pharmaceutically acceptable salt or prodrug.
2. the method that treatment is selected from following disease in the mammal for having this to need: syndrome, β hemoglobin before cancer, cancer Disease, drepanocytosis, sickle-cell anemia and beta Thalassemia comprising to the mammal dosage treatment effective amount Formula (IVbbr) compound:
Wherein:
X41bbrAnd X42bbrIndependently selected from :-CN, methyl, fluorine, chlorine, bromine and iodine；
Y4bbrIt is selected from: S and NH；
R41bbrIt is selected from:
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo, C1-4Alkyl oxy ,- OH、-COOH、-NH2-N(H)C1-4Alkyl ,-N (C1-4Alkyl)2With-CN,
C1-4Alkyl oxy,
Replaced 1-4 C by fluorine1-4Alkyl oxy,
-N(H)C1-4Alkyl,
-N(C1-4Alkyl)2,
-SC1-4Alkyl,
Aryl,
The aryl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-OH ,-NH2With-CN,
C1-4Alkoxy,
- CN,
Oxo,
- OH,
-NO2, and
-NH2,
Heteroaryl,
The heteroaryl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-OH ,-NH2With-CN,
C1-4Alkoxy,
- CN,
Oxo,
- OH,
-NO2, and
-NH2,
Naphthenic base,
The naphthenic base replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-OH ,-NH2With-CN,
C1-4Alkoxy,
- CN,
Oxo,
- OH,
-NO2, and
-NH2；
R43bbrIt is selected from:
C1-4Alkyl,
Phenyl,
The phenyl replaced by 1-2 substituent groups independently selected from the following:
Fluorine ,-CH3、-CF3, chlorine ,-C (O) phenyl, pyrrolidinyl ,-P (O) (CH3)2、-C(O)NH2、-S(O)2NHCH3、- OCH2CH2N(CH3)2With-CH2C(O)NH2,
Thienyl,
Piperidyl,
Pyridine, and
The pyridine replaced by 1 or 2 substituent group independently selected from the following:
Fluorine ,-CH3、-CF3With-OCH3；
R44bbrAnd R45bbrIndependently selected from:
Hydrogen,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Phenyl, morpholino, triazolyl, imidazole radicals, pyrrolidinyl ,-OC (O) NH2、-OCH2CH2NH2、-ONHC(NH2)NH2、- NHCH2C(CH3)3、-NOCH3、-NHOH、-NHCH2CH2F、-N(CH3)CH2CH2OCH3、-N(CH2CH3)2、-NCH(CH2OH)2、-N (CH2CH2OH)2、-NHCH2CH2OH、-NHCH2CH2NH2、-N(CH3)C(CH3)2CH2OH、-NHCH2CH3、-NHCH2CH2OCH3、-N (CH3)CH2CH2OH、-NHC(O)C(O)NH2、-N(CH3)CH2CH2CH2OH、-N(CH3)CH2CH(OH)CH2OH、-N(CH3) CH2CH2NH2, oxo ,-NHCH2C(CH3)2CH2OH、-OH、-NH2、-NHCH3、-NHCH2CH2CH2OH、-N(CH3)2、-N(CH3) CH2CH3、-NHOC(CH3)2NH2、-N(CH3)CH2Cyclopropyl ,-NHCH2Cyclopropyl ,-NH oxetanyl ,-NCH2CH2Three Azoles, piperazinyl, piperidyl, pyrazolyl, azepine cycloheptatriene base, azetidinyl, methoxyl group and cyclopropylamino,
The wherein phenyl, morpholino, triazolyl, imidazole radicals, azepine cycloheptatriene base, azetidinyl, pyrrolidinyl, piperazine Piperazine base, piperidyl, oxetanyl, cyclopropyl and pyrazolyl are optionally taken by 1-4 substituent groups independently selected from the following Generation: methyl, fluorine ,-NH2、-N(CH3)2, hydroxymethyl, oxo ,-OH and-CH2NH2,
Naphthenic base,
The naphthenic base independently replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH,
C1-6Alkyl, and
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine and chlorine；
Heterocyclylalkyl and
The Heterocyclylalkyl replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-OH ,-NH2With-CN,
Aryl,
C1-4Alkoxy,
The C replaced by 1-4 substituent groups independently selected from the following1-4Alkoxy: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- CN,
Oxo,
- OH,
- COOH,
-NO2,
-NH2, and
SO2NH2, or
R44bbrAnd R45bbrThe nitrogen connected to them and optionally 1-3 additional hetero atoms selected from O, N and S are formed together miscellaneous Naphthenic base is optionally replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, C1-4Alkoxy, oxo, phenyl, cycloalkanes Base, Heterocyclylalkyl, methyl heterocycles alkyl-,-OH ,-NH2、-N(H)C1-5Alkyl, amino-heterocycles alkyl-,-N (C1-5Alkyl)2、- CN、-N(C1-4Alkyl) (CH2OCH3) and-NHC that is replaced by 1 or 2 substituent group independently selected from the following1-4Alkyl: oxo, NH2With-OH,
Aryl,
Naphthenic base,
Heterocyclylalkyl,
The Heterocyclylalkyl replaced by 1-9 substituent groups independently selected from the following: C1-6Alkyl ,-C1-6Alkyl OH, fluorine ,-C1-6Alkane Base NH2, chlorine, bromine, iodine, oxo ,-OH ,-NH2With-CN,
C1-4Alkoxy,
The C replaced by 1-4 substituent groups independently selected from the following1-4Alkoxy: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- CN,
Oxo,
- OH,
-OP(O)(OH)2,
- COOH,
-CONH2,
-NO2,
-NH2,
-N(H)C1-5Alkyl,
- N (H) C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Fluorine, chlorine, bromine, iodine, C1-4Alkoxy, oxo, phenyl, naphthenic base, amino C1-4Alkoxy, Heterocyclylalkyl, methyl heterocycles alkane Base-,-OH ,-NH2、-N(H)C1-4Alkyl ,-N (C1-4Alkyl)2With-CN,
- O oxetanyl,
-ONHC(NH)NH2,
- NH cyclopropyl,
- NH oxetanyl,
-N(C1-5Alkyl)2,
-S(O)2CH2CH3,
S(O)2CH2CH2CH3,
-S(O)2CH3,
-SO2NH2,
-S(O)2Phenyl,
Benzoyl,
Benzylamino,
Propylpyrrolidinyl,
Methylcyclopropyl groups,
Cyclobutylamino,
Cyclobutyl-N (CH3)-,
Piperidyl,
Imidazole radicals,
Morpholinyl,
Morpholinyl methyl,
Methyl piperazine ylmethyl,
Methyl piperazine base,
Pyrrolidinyl,
Pyrrolidinylmethyl,
(methoxypyridylmethyl) amino,
Methylpyrrole alkyl,
Difluoropyrrolidin base,
Alkyl dimethyl pyrrole,
(methylcyclopropylmethyl) amino,
Hydroxymethyl-pyrrolidine base,
Fluoropyrrolidine base,
Fluorophenyl methyl amino,
Piperizinylmethyl,
Oxazolidinyl,
(methy oxetane ylmethyl) amino,
(methyl-cyclobutyl methyl) amino,
Oxoimidazolidinyl, and
2- hydroxyethylpiperidine base；
On condition that:
X41bbrAnd X42bbrIt is not all hydrogen, and
R44bbrAnd R45bbrIt is not all hydrogen；
Or its pharmaceutically acceptable salt or prodrug.
3. method according to claim 2, wherein the mammal is people.
4. inhibiting the active method of DNMT1 in the mammal for thering is this to need comprising have to the mammal drug treatment Formula as claimed in claim 2 (IVbbr) compound of effect amount or its pharmaceutically acceptable salt.
5. method according to claim 4, wherein the mammal is people.
6. the method according to claim 1, wherein the compound is selected from:
2- [(6- amino -3,5- dicyano -4- ethylpyridine -2- base) sulfanyl] -2- phenyl-acetamides；
(R)-[(6- amino -3,5- dicyano -4- ethylpyridine -2- base) sulfanyl] -2- phenyl-acetamides；
2- { [3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base] sulfanyl } -2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- { [3,5- dicyano -4- cyclopropyl -6- (4- ethyl -1,4- Diazesuberane -1- base) pyridine -2- base] sulfane Base } -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- propyl -1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- { [3,5- dicyano -4- ethyl -6- (4- ethyl -1,4- Diazesuberane -1- base) pyridine -2- base] sulfanyl } - 2- phenyl-acetamides；
2- { [3,5- dicyano -4- ethyl -6- (5- oxo -1,4- Diazesuberane -1- base) pyridine -2- base] sulfanyl } - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- morpholino pyridine -2- base) sulfenyl) -2- (pyridin-4-yl) acetamide；
2- { [3,5- dicyano -4- ethyl -6- (4- methyl -3- oxypiperazin -1- base) pyridine -2- base] sulfanyl } -2- (pyrrole Pyridine -4- base) acetamide；
2- [(3,5- dicyano -4- ethyl -6- { methyl [2- (morpholine -4- base) ethyl] amino } pyridine -2- base) sulfanyl] -2- Phenyl-acetamides；
2- { [3,5- dicyano -4- ethyl -6- (4- propylpiperazine -1- base) pyridine -2- base] sulfanyl } -2- phenyl-acetamides；
2- ({ 3,5- dicyano -4- ethyl -6- [4- (piperidin-4-yl) piperazine -1- base] pyridine -2- base } sulfanyl) -2- phenyl Acetamide；
2- ({ 3,5- dicyano -4- cyclopropyl -6- [3- (hydroxymethyl) piperazine -1- base] pyridine -2- base } sulfanyl) -2- phenyl Acetamide；
2- { [3,5- dicyano -4- cyclopropyl -6- (3- oxypiperazin -1- base) pyridine -2- base] sulfanyl } -2- phenylacetyl Amine；
2- ({ 3,5- dicyano -4- cyclopropyl -6- [4- (morpholine -4- base) piperidin-1-yl] pyridine -2- base } sulfanyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- (2,8- diaza spiro [4.5] decyl- 8- yl) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- cyclopropyl -6- (3- (dimethylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- cyclopropyl -6- (3- methylpiperazine-1-yl) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (2- (hydroxymethyl) morpholino) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- cyclopropyl -6- (2,6- thebaine generation) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (3- (dimethylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((6- (4- (amino methyl) -4- hydroxy piperidine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (3- (methylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((6- (3- amino piperidine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (dimethylamino) pyridine -2- base) sulfenyl) -2- (pyridin-4-yl) acetyl Amine；
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (pyridin-4-yl) acetamide；
2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (4- (dimethylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- cyclopropyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- (pyridin-4-yl) acetamide；
2- ((3,5- dicyano -4- cyclopropyl -6- (1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (pyridine - 4- yl) acetamide；
2- ((3,5- dicyano -4- cyclopropyl -6- ((R) -3- hydroxy piperidine -1- base) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- (3,5- dicyano -4- cyclopropyl -6- ((S) -3- hydroxy piperidine -1- base) pyridine -2- base sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- cyclopropyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (pyridine - 4- yl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- ethyl piperazidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (1- oxa- -6- azaspiro [3.4] octyl- 6- yl) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((6- (4- (3- aminopropyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- ethyl -6- (1,7- diaza spiro [3.5] nonyl- 1- yl) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- cyclopropyl -6- (4- (pyrrolidin-1-yl methyl) piperidin-1-yl) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
(R) -2- ((3,5- dicyano -6- (1,4- Diazesuberane -1- base) -4- ethylpyridine -2- base) amino) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- cyclopropyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- (2,7- diaza spiro [3.5] nonyl- 7- yl) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- ethyl -6- (2,6- diaza spiro [3.4] octyl- 6- yl) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- cyclopropyl -6- (1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) propionamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (2- oxo-imidazole alkane -1- base) piperidin-1-yl) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- hydroxy piperidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- (3- oxypiperazin -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- [(6- amino -3,5- dicyano -4- cyclopropyl -2- pyridyl group) sulfanyl] -2- phenvl-acetamide；
2- ((3,5- dicyano -4- ethyl -6- (methylamino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- methoxy ethyl) (methyl) amino) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- ethyl -6- (3- methoxyl group azetidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- ethyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- morpholino pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- [[6- (azetidine -1- base) -3,5- dicyano -4- ethyl -2- pyridyl group] sulfanyl] -2- phenvl-acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- oxo-piperidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (1'- (2- hydroxyethyl)-[4,4'- joins piperidines] -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((3S, 5R) -3,5- lupetazin -1- base) -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((6- (8- azabicyclo [3.2.1] oct-3-yl (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (2- (hydroxymethyl) morpholino) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
(R) -2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
(R) -2- [(3,5- dicyano -4- ethyl -6- morpholino -2- pyridyl group) sulfanyl] -2- phenvl-acetamide；
2- { [3,5- dicyano -4- ethyl -6- (5- methyl-1,4- Diazesuberane -1- base) pyridine -2- base] sulfanyl } - 2- phenyl-acetamides；
2- ({ 3,5- dicyano -4- ethyl -6- [4- (2- methoxy ethyl) -1,4- Diazesuberane -1- base] pyridine -2- Base } sulfanyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxypropyl) -1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- [4- (6- { [carbamoyl (phenyl) methyl] sulfanyl } -3,5- dicyano -4- ethylpyridine -2- base) -1,4- two Azepan -1- base] methyl acetate；
2- { [3,5- dicyano -4- cyclopropyl -6- (4- methyl -5- oxo -1,4- Diazesuberane -1- base) pyridine -2- base] Sulfanyl } -2- phenyl-acetamides；
2- { [3,5- dicyano -4- cyclopropyl -6- (5- oxo -1,4- Diazesuberane -1- base) pyridine -2- base] sulfane Base } -2- phenyl-acetamides；
2- { [3,5- dicyano -4- ethyl -6- (4- methyl -5- oxo -1,4- Diazesuberane -1- base) pyridine -2- base] sulphur Alkyl } -2- phenyl-acetamides；
2- { [3,5- dicyano -6- (1,4- Diazesuberane -1- base) -4- ethylpyridine -2- base] sulfanyl } -2- phenyl second Amide；
2- ({ 3,5- dicyano -6- [4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base] -4- (2,2,2- trifluoro second Base) pyridine -2- base } sulfanyl) -2- phenyl-acetamides；
(2R) -2- ({ 3,5- dicyano -4- ethyl -6- [4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base] pyridine - 2- yl } amino) -2- phenyl-acetamides；
2- ({ 6- [(3S) -3- amino-pyrrolidine -1- base] -3,5- dicyano -4- cyclopropyl pyridine -2- base } sulfanyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- (2,9- diaza spiro [5.5] hendecane -9- base) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (hexahydro -1H- pyrrolo- [1,2-a] [1,4] diazacyclo heptantriene -2 (3H) - Base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (2- methyl -2,9- diaza spiro [5.5] hendecane -9- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (2- (Cvclopropvlmethvl) -2,9- diaza spiro [5.5] hendecane -9- base) -4- ethyl pyrrole Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- (3- (dimethylamino) propyl) piperazine -1- base) -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-3-yl) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((6- ([4,4'- joins piperidines] -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((6- (4- (2- amino-ethyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((6- (4- (3- aminopropyl) piperazine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- cyclopropyl -6- (4- ((4- methylpiperazine-1-yl) methyl) piperidin-1-yl) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((6- (4- Acetylpiperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (dimethylamino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- (4- chlorphenyl) -2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxyethyl) piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- [(3,5- dicyano -4- cyclopropyl -6- morpholino -2- pyridyl group) sulfanyl] -2- phenvl-acetamide；
2- ((6- (4- benzoyl-piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- ((5S, 6S) -6- hydroxyl -1- (methyl sulphonyl) -1,8- diaza spiro [4.5] Decyl- 8- yl) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4,4- difluoropiperdin -1- base) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
(R) -2- ((3,5- dicyano -4- ethyl -6- ((R) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- (furans -2- base) -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((6- (4- amino -4- methyl piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) piperidin-4-yl) acetamide；
(2S) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) propionamide；
2- ((6- (4- (3- amino oxetanes -3- carbonyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
4- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) piperidin-4-yl) tetrahydro -2H- pyrans -4- formamide；
2- ((6- (4- (4- amino tetrahydro -2H- pyrans -4- carbonyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base) -4-methoxypyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((6- ((2- amino-ethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((6- ((2- amino -2- oxoethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (3- hydroxy azetidine -1- base) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- (3,5- dicyano -4- ethyl -6- ((2- hydroxyethyl) (methyl) amino) pyridine -2- base sulfenyl) -2- phenylacetyl Amine；
2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) piperidin-4-yl) -2- methyl propanamide；
2- ((6- (4- (2- amino ethoxy) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl Acetamide；
Biphosphate 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) Pyrrolidin-3-yl ester；
Biphosphate 2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) (methyl) amino) ethyl ester；
Biphosphate 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) Azetidine -3- base ester；
(2S) -2- amino -3 Methylbutanoic acid 2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyan Base -4- ethylpyridine -2- base) piperidin-4-yl) oxygroup) ethyl ester；
Biphosphate 2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) piperidin-4-yl) oxygroup) ethyl ester；
Biphosphate 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) Piperidin-4-yl ester；
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (piperidin-4-yl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (sulfonyl propyl base) piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- ethyl -6- (4- (phenyl sulfonyl) piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- ethyl -6- ((R) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- (2- oxa- -6- azaspiro [3.4] octyl- 6- yl) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
(R) -2- ((3,5- dicyano -4- ethyl -6- (4- ethyl -1,4- Diazesuberane -1- base) pyridine -2- base) ammonia Base) -2- phenyl-acetamides；
(R) -2- ((3,5- dicyano -4- ethyl -6- (4- (3- (pyrrolidin-1-yl) propyl) -1,4- Diazesuberane -1- Base) pyridine -2- base) amino) -2- phenyl-acetamides；
2- (3,5- dicyano -4- cyclopropyl -6- (3- hydroxy piperidine -1- base) pyridine -2- base sulfenyl) -2- phenyl-acetamides；
2- ((the chloro- 4- ethyl -6- of 3,5- bis- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -6- (1,1- sulfur dioxide morpholino) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (methyl (2- (piperazine -1- base) ethyl) amino) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
(R) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((6- ((2- (4- (amino methyl) -4- hydroxy piperidine -1- base) ethyl) (methyl) amino) -3,5- dicyano -4- second Yl pyridines -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((4- cyano -3- (1,4- Diazesuberane -1- base) -6,7- dihydro -5H- cyclopenta [c] pyridine -1- base) Sulfenyl) -2- phenyl-acetamides；
2- ((6- (4- (1H- imidazoles -1- base) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (pyridin-4-yl methyl) piperazine -1- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -6- (2- (dimethylamino) ethyoxyl) -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine -2- base) piperazine Pyridine -3- base) amino) acetic acid；
2- ((3,5- dicyano -4- ethyl -6- (4- (oxazole -2- ylmethyl) piperazine -1- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((6- (4- ((1H- pyrroles -2- base) methyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -6- (- 2 (1H)-yl of 3,4- dihydro -2,7- benzodiazine) -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (pyridine -3- Base) acetamide；
2- ((6- (4- ((1H- pyrroles -3- base) methyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (isoxazole -3- ylmethyl) piperazine -1- base) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (oxazole -5- ylmethyl) piperazine -1- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (isoxazole -4- ylmethyl) piperazine -1- base) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
3- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) piperidin-4-yl) oxetanes -3- formamide；
2- ((6- (4- ((1H- pyrazoles -4- base) methyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((6- (4- ((1H- imidazoles -5- base) methyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (1- hydroxy-2-methyl propyl- 2- yl) piperazine -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((6- (4- ((1H- imidazoles -2- base) methyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -6- (dimethylamino) -4-methoxypyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (dimethylamino) -4- ethoxy pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyoxyl -6- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxy-2-methyl propyl) -1,4- Diazesuberane -1- base) pyrrole Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (thiazole -5- ylmethyl) piperazine -1- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- (4- fluorophenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (isothiazole -4- ylmethyl) piperazine -1- base) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (4- fluorophenyl) acetamide；
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (5- fluorine pyridine -2- base) acetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- (4- (furans -3- ylmethyl) piperazine -1- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((2- morpholinoethyl) sulfenyl) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- methyl-1,4- Diazesuberane -1- base) -4- (methylsulfany) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((the chloro- 4- ethyl -6- of 3,5- bis- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (hexahydropyrrolo simultaneously [3,4-b] [1,4] oxazines -6 (2H)-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (5- picoline -2- base) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (6- fluorine pyridine -2- base) acetamide；
2- ((3,5- dicyano -6- (4- (dimethylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- (4- fluorine Phenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (4- picoline -2- base) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (3-Methoxy Pyridine -2- base) acetamide；
2- ((3,5- dicyano -6- (4- (dimethylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- (2,4- Difluorophenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- (5- fluorine Pyridine -2- base) acetamide；
2- ((3,5- dicyano -4- ethyoxyl -6- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) propionamide；
2- ((3,5- dicyano -6- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base) -4- propoxyl group pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (4-methoxypyridine -2- base) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (2- methyl -2,8- diaza spiro [4.5] decyl- 8- yl) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- (dimethylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- (3,4- Difluorophenyl) acetamide；
1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidines -4- Formamide；
2- ((3,5- dicyano -6- ((2- (dimethylamino) ethyl) sulfenyl) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -6- ((3S, 4R) -3,4- dihydroxy pyrrolidine -1- base) -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (3- fluorine pyridine -2- base) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (5- methoxypyridine -2- base) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (1- hydroxy-2-methyl propyl- 2- yl) piperazine -1- base) pyridine -2- base) sulphur Base) -2- (4- fluorophenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (3- (trifluoromethyl) phenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxyl-oxethyl) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (2- fluorine pyridin-3-yl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (6- fluorine pyridin-3-yl) acetamide；
3- ((6- (2- amino -2- oxo -1- phenylethyl sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) ammonia Base) propionamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (oxetanes -3- base oxygroup) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- ((2,2- bis-fluoro ethyls) amino) -4- methyl piperidine -1- base) -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (4- (trifluoromethyl) phenyl) acetamide；
2- ((6- (4- aminopiperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((6- ((2- amino -2- oxoethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- ethyl -6- (pyrrolo- [3,4-c] pyrazoles -5 (1H, 4H, 6H)-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (5- methoxypyridine -2- base) Acetamide；
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (5- picoline -2- base) second Amide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (2- fluorine pyridin-4-yl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- hydroxyl -4- (hydroxymethyl) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (2- oxo -3- oxa- -1,8- diaza spiro [4.5] decyl- 8- yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((6- (4- amino -4- (hydroxymethyl) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((6- (4- (amino methyl) -4- hydroxy piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- (3- benzoylphenyl) -2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxyethyl) -1,4- diaza cycloheptyl Alkane -1- base) pyridine -2- base) sulfenyl) acetamide；
2- (4- benzoylphenyl) -2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxyethyl) -1,4- diaza cycloheptyl Alkane -1- base) pyridine -2- base) sulfenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (2- picoline -4- base) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (3- (pyrrolidin-1-yl) phenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (3- fluorine pyridin-4-yl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (2,5- difluoro pyridine -4- base) acetamide；
2- ((3,5- dicyano -6- (4- (2,5- dioxo alkyl imidazole -1- base) piperidin-1-yl) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
4- amino -1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) Piperidines -4- formamide；
2- ((3,5- dicyano -6- (4- (2,5- dioxo pyrrolidin -1- base) piperidin-1-yl) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides (isomers 1)；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides (isomers 2)；
2- ((3,5- dicyano -4- ethyl -6- (2- oxo -1- oxa- -3,8- diaza spiro [4.5] decyl- 8- yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) -4- hydroxyl Piperidines -4- formamide；
Carbamic acid 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) Azetidine -3- base ester；
2- ((3,5- dicyano -6- (4- (2,4- dioxo oxazolidine -3- base) piperidin-1-yl) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
3- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) Amino) -2- hydroxy-2-methyl propionamide；
2- ((3,5- dicyano -4- ethyl -6- (3- (hydroxymethyl) azetidine -1- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- (3,5- dicyano -4- ethyl -6- (piperazine -1- base) pyridine -2- base sulfenyl) -2- (thiene-3-yl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (5- picoline -3- base) acetamide；
2- ((6- (4- (3- amino -2- oxo-pyrrolidine -1- base) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
(2S) -2- amino -3 Methylbutanoic acid 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- Ethylpyridine -2- base) piperidin-4-yl ester；
(2S) -2- amino -3 Methylbutanoic acid 2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano - 4- ethylpyridine -2- base) (methyl) amino) ethyl ester；
2,2'- ((3,5- dicyano -4- ethylpyridine -2,6- diyl) bis- (sulfane diyls)) bis- (2- phenyl-acetamides)；
(2S) -2- amino -3 Methylbutanoic acid (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano - 4- ethylpyridine -2- base) azetidine -3- base) methyl ester；
2- ((6- (3- aminoazetidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- picoline -2- base) sulfenyl) -2- phenyl-acetamides；
N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidines - 4- yl) -2- hydroxyl acetamide；
N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) azepine Cyclobutane -3- base) -2- hydroxyl acetamide；
2- ((3- cyano -4- ethyl -5- methyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (5- methyl -2,5- diazabicyclo [2.2.1] hept- 2- yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (2- (pyrrolidin-1-yl) ethyl) piperazine -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides -2-d；
(R) -2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides -2-d；
2- ((6- (4- (4- benzoyl bromide) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- cyano piperidine -1- base) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
(S) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((6- (4- amino -4- methyl piperidine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (pyridine -2- Base) acetamide；
2- ((3,5- bis- chloro- 4- ethyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
(1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidines -4- Base) t-butyl carbamate；
2- ((6- (3- (2- amino -2- oxoethyl) azetidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
(2R) -2- amino -3 Methylbutanoic acid 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- Ethylpyridine -2- base) azetidine -3- base ester；
2- ((3,5- dicyano -4- ethyl -6- (methyl ((5- oxo -4,5- dihydro -1H-1,2,4- triazole -3- base) methyl) ammonia Base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((6- (((4H-1,2,4- triazole -3- base) methyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyoxyl -6- picoline -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4,6- parvoline -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((6- ((2- (4H-1,2,4- triazole-4-yl) ethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((6- (((1H- pyrazole-3-yl) methyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -6- (6,7- dihydro -1H- [1,2,3] triazol [4,5-c] pyridine -5 (4H)-yl) -4- ethyl pyrrole Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((6- (((1H- imidazoles -2- base) methyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((6- (((1H- imidazoles -5- base) methyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
(2R) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) propionamide；
4- (2- amino -1- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) -2- oxoethyl) benzamide；
2- ((3,5- dicyano -4- cyclopropyl -6- (3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- (3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
(2R) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl Pyridine -2- base) piperidin-4-yl) propionamide；
2- ((6- ((2- amino-ethyl) (methyl) amino) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine - 2- yl) piperidin-4-yl) -2- methyl propanamide；
4- (2- amino -1- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- oxoethyl) Benzamide；
2- (6- (4- amino piperidine -1- base) -3- cyano -4- ethyl -5- picoline -2- base sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (4- (N- Methylsulfamoyl) phenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (the fluoro- 1,4- Diazesuberane -1- base of 6-) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((6- (4- amino -3,3- difluoropiperdin -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl Acetamide；
(1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) -3,3- two Fluorine resources -4- base) t-butyl carbamate；
2- ((3,5- dicyano -4- cyclopropyl -6- ((2- hydroxyethyl) (methyl) amino) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- cyclopropyl -6- (3- hydroxy azetidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl second Amide；
1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) pyrrolidines - 3- formamide；
2- ((6- ((3- aminopropyl) (methyl) amino) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- cyclopropyl -6- ((2- (3- hydroxy azetidine -1- base) -2- oxoethyl) (methyl) ammonia Base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((6- (4- ((2- amino -2- oxoethyl) amino) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((6- ((2- amino -2- oxoethyl) (methyl) amino) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
Carbamic acid 2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine -2- Base) (methyl) amino) ethyl ester；
(2R) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) -3- hydroxypropanamide；
(2S) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) -3- hydroxypropanamide；
2- (4- (2- amino -2- oxoethyl) phenyl) -2- (3,5- dicyano -4- ethyl -6- (4- methyl-1,4- diazacyclo Heptane -1- base) pyridine -2- base sulfenyl) acetamide；
2- (4- (2- amino -2- oxoethyl) phenyl) -2- (3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- Base sulfenyl) acetamide；
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (4- (N- Methylsulfamoyl) Phenyl) acetamide；
2- ((3,5- dicyano -6- (dimethylamino-d6) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
(R) -2- ((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
(R) -2- ((3,5- dicyano -6- (4- (dimethylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- (3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base sulfenyl) -2- (3- (2- (dimethylamino) second Oxygroup) phenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (neopentyl amino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- (4- fluorine Phenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (the fluoro- 4- of 3- (neopentyl amino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- (4- (trifluoromethyl) Phenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
(R) -2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((6- ((2- amino -2- oxoethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides；(single enantiomer)
Biphosphate (3S) -1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) pyrrolidin-3-yl ester；
Biphosphate (3R) -1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) pyrrolidin-3-yl ester；
Biphosphate (S) -1- (6- (((S) -2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) pyrrolidin-3-yl ester；
Biphosphate (S) -1- (6- (((R) -2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) pyrrolidin-3-yl ester；
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (3- (solutions of dimethyl phosphoryl base) benzene Base) acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (3- (diformazan Base phosphoryl) phenyl) acetamide；
Biphosphate (R) -2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) (methyl) amino) ethyl ester；
(R) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (4- Methoxyphenyl) acetamide；
(R) -2- (4- chlorphenyl) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- Base) sulfenyl) acetamide；
(R) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (4- Fluorophenyl) acetamide；
Biphosphate (S) -1- (6- (((R) -2- amino -1- (4- fluorophenyl) -2- oxoethyl) sulfenyl) -3,5- dicyano -4- Ethylpyridine -2- base) pyrrolidin-3-yl ester；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (4- fluorobenzene Base) acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (2,6- bis- Fluorophenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (2,3- bis- Fluorophenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (2,4- bis- Fluorophenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- ((S) -2- (hydroxymethyl) pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((2- hydroxyethyl) (methyl) amino) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((2- hydroxy-2-methyl propyl) (methyl) amino) piperidin-1-yl) pyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-1-yl methyl) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((2- methoxyl group -2- methyl-propyl) amino) piperidin-1-yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((2- hydroxy-2-methyl propyl) amino) piperidin-1-yl) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- (Cyclobutylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- ethyl -6- (4- (((3- methy oxetane -3- base) methyl) amino) piperidin-1-yl) Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((R) -2- methylpyrrolidin- 1- yl) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- ((2R, 5S) -2,5- dimethyl pyrrolidine -1- base) piperidin-1-yl) -4- ethylpyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((S) -2- methylpyrrolidin- 1- yl) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- (cyclobutyl (methyl) amino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- (6- (4- (benzylamino) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- (4- (((6- methoxypyridine -2- base) methyl) amino) piperidin-1-yl) pyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((S) -3- fluoropyrrolidine -1- base) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (methyl (2- ((R) -2- methylpyrrolidin- 1- yl) ethyl) amino) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((R) -3- fluoropyrrolidine -1- base) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- ((2S, 5S) -2,5- dimethyl pyrrolidine -1- base) piperidin-1-yl) -4- ethylpyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (methyl (2- ((S) -2- methylpyrrolidin- 1- yl) ethyl) amino) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((R) -2- (hydroxymethyl) pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- (dimethylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- (4- fluorine Phenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (((1- methyl-cyclobutyl) methyl) amino) piperidin-1-yl) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (((6- methoxypyridine -3- base) methyl) amino) piperidin-1-yl) pyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- (3,5- dicyano -4- ethyl -6- ((2- (ethylamino) ethyl) (methyl) amino) pyridine -2- base sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- ((4- methylpiperazine-1-yl) methyl) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (methyl (2- (methylamino) ethyl) amino) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -6- (4- ((2R, 5R) -2,5- dimethyl pyrrolidine -1- base) piperidin-1-yl) -4- ethylpyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (((1- methylcyclopropyl groups) methyl) amino) piperidin-1-yl) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((4- luorobenzyl) amino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((S) -2- (hydroxymethyl) pyrrolidin-1-yl) ethyl) (methyl) amino) Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- (3,5- dicyano -6- ((2- ((2S, 5R) -2,5- dimethyl pyrrolidine -1- base) ethyl) (methyl) amino) -4- second Yl pyridines -2- base sulfenyl) -2- phenyl-acetamides；
2- ((6- ((2- (azepan -1- base) ethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (methyl (2- (piperidin-1-yl) ethyl) amino) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((R) -2- (hydroxymethyl) pyrrolidin-1-yl) ethyl) (methyl) amino) Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- (3,5- dicyano -4- ethyl -6- ((2- (ethyl (methyl) amino) ethyl) (methyl) amino) pyridine -2- base sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((2- ((2R, 5R) -2,5- dimethyl pyrrolidine -1- base) ethyl) (methyl) amino) -4- second Yl pyridines -2- base) sulfenyl) -2- phenyl-acetamides；
2- (3,5- dicyano -4- ethyl -6- ((2- ((S) -3- hydroxyl pyrrolidine -1- base) ethyl) (methyl) amino) pyridine -2- Base sulfenyl) -2- phenyl-acetamides；
2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperazine Pyridine -4- base) amino) -2 Methylpropionic acid methyl esters；
2- ((3,5- dicyano -4- ethyl -6- (methyl (2- (neopentyl amino) ethyl) amino) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- (3,5- dicyano -4- ethyl -6- (methyl (2- (1- methylcyclopropyl groups amino) ethyl) amino) pyridine -2- base sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((2- ((2S, 5S) -2,5- dimethyl pyrrolidine -1- base) ethyl) (methyl) amino) -4- second Yl pyridines -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((2- methoxy ethyl) amino) ethyl) (methyl) amino) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((2- methoxyl group -2- methyl-propyl) (methyl) amino) piperidin-1-yl) pyrrole Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((2- (dimethylamino) ethyl) (methyl) amino) -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- (3,5- dicyano -4- ethyl -6- ((2- ((R) -3- hydroxyl pyrrolidine -1- base) ethyl) (methyl) amino) pyridine -2- Base sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((2- fluoro ethyl) amino) ethyl) (methyl) amino) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- (3,3- difluoropyrrolidin -1- base) piperidin-1-yl) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperazine Pyridine -4- base) amino) acetic acid；
2- ((6- ((3- Aminocyclobutyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl Acetamide；
(R) -2- (3,5- dicyano -4- ethyl -6- (methyl ((R)-tetrahydrofuran -3- base) amino) pyridine -2- base sulfenyl) -2- Phenyl-acetamides；
(S) -2- (3,5- dicyano -4- ethyl -6- (methyl ((R)-tetrahydrofuran -3- base) amino) pyridine -2- base sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- morpholino piperidin-1-yl) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxyethyl) -3- oxypiperazin -1- base) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- (4- fluorine Phenyl) acetamide；
(R) -2- ((6- ((3S, 4R) -4- amino -3- fluorine resources -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (3- fluoro- 4- (methylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
Rel-2- ((6- (trans-) -4- amino -3- fluorine resources -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
(R) -2- ((6- ((3R, 4S) -4- amino -3- fluorine resources -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (the fluoro- 4- of 3- ((2- methoxy ethyl) amino) piperidin-1-yl) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (methyl (2- (pyrrolidin-1-yl) ethyl) amino) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -6- (3- ((dimethylamino) methyl) pyrrolidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((2- hydroxy-2-methyl propyl) amino) piperidin-1-yl) pyridine -2- base) Sulfenyl) -2- (4- fluorophenyl) acetamide；
(R) -2- ((6- ((3S, 4R) -4- amino -3- hydroxy piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((2- (diethylamino) ethyl) (methyl) amino) -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((2- ((R) -3- (dimethylamino) pyrrolidin-1-yl) ethyl) (methyl) amino) -4- second Yl pyridines -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((2- ((S) -3- (dimethylamino) pyrrolidin-1-yl) ethyl) (methyl) amino) -4- second Yl pyridines -2- base) sulfenyl) -2- phenyl-acetamides；
(R) -2- ((6- ((3R, 4R) -4- amino -3- fluorine resources -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
(R) -2- ((6- ((3S, 4S) -4- amino -3- fluorine resources -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (3- (methylamino) pyrrolidin-1-yl) pyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- (4- fluorophenyl) acetyl Amine；
(R) -2- ((6- ((3R, 4R) -4- amino -3- hydroxy piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((6- ((R) -3- amino-pyrrolidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((6- (3- (amino methyl) pyrrolidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- ethyl -6- (4- (methylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- (4- fluorobenzene Base) acetamide；
2- ((3,5- dicyano -6- (4- (cyclopropylamino) -3- fluorine resources -1- base) -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((6- ((S) -3- amino-pyrrolidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((6- ((2- ((R) -3- amino-pyrrolidine -1- base) ethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
3,5- dicyano -6- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- (4- Fluorophenyl) acetamide；
(S) -2- ((6- ((3S, 4R) -4- amino -3- fluorine resources -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (neopentyl amino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- (4- (three Methyl fluoride) phenyl) acetamide；
((3S, 4R) -1- (6- (((R) -2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) -3- hydroxy piperidine -4- base) t-butyl carbamate；
Rel- (cis-) -1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) -3- fluorine resources -4- base) t-butyl carbamate；
2- ((6- ((2- ((S) -3- amino-pyrrolidine -1- base) ethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
((3R, 4S) -1- (6- (((R) -2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) -3- hydroxy piperidine -4- base) t-butyl carbamate；
Rel- (cis-) -1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) -3- fluorine resources -4- base) t-butyl carbamate；
2- ((3,5- dicyano -6- ((S) -3- (dimethylamino) pyrrolidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
(S) -2- ((6- ((3R, 4S) -4- amino -3- fluorine resources -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- ((2- hydroxy-2-methyl propyl) amino) pyrrolidin-1-yl) pyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
((3R, 4R) -1- (6- (((R) -2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) -3- hydroxy piperidine -4- base) t-butyl carbamate；
2- ((3,5- dicyano -6- ((S) -3- (dimethylamino) pyrrolidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- (4- fluorophenyl) acetamide；
Rel-2- ((cis- -4- amino -3- fluorine resources -1- base of 6-) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (methylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -6- (4- (dimethylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- ethyl -6- (4- (ethyl (methyl) amino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (neopentyl amino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- ethyl -6- (4- (methyl (neopentyl) amino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -6- (4- (cyclopropylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- ethyl -6- (4- ((2- methoxy ethyl) amino) piperidin-1-yl) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- ((2,2- bis-fluoro ethyls) amino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((R) -2- ((neopentyl amino) methyl) morpholino) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -6- (2- ((dimethylamino) methyl) morpholino) -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -6- (2- ((diethylamino) methyl) morpholino) -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- (2- (pyrrolidin-1-yl methyl) morpholino) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
(R) -2- ((6- ((R) -2- (amino methyl) morpholino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((6- (2- (amino methyl) morpholino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (2- ((methylamino) methyl) morpholino) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((6- ((R) -2- (amino methyl) morpholino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -6- (3- ((dimethylamino) methyl) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (3- ((methylamino) methyl) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((S) -2- ((neopentyl amino) methyl) morpholino) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- ((neopentyl amino) methyl) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- amino-N- (((2S) -4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine-2- base) morpholine -2-yl) methyl)-2- methyl propanamide；
2- ((6- ((S) -3- (amino methyl) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -6- ((R) -2- ((diethylamino) methyl) morpholino) -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- amino-N- (((2R) -4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine-2- base) morpholine -2-yl) methyl)-2- methyl propanamide；
2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- (3- fluorine pyridine -2- Base) acetamide；
2- ((6- ((S) -2- (amino methyl) morpholino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- amino-N- (((3S) -1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidines -3- base) methyl) -2- methyl propanamide；
2- amino-N- (((3S) -1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidines -3- base) methyl) acetamide；
2- amino-N- (((2R) -4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine-2- base) morpholine -2-yl) methyl) acetamide；
2- ((6- ((R) -3- (amino methyl) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- (4- Fluorophenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((R) -3- ((neopentyl amino) methyl) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- (4- fluorophenyl) acetamide；
2- amino-N- (((2S) -4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine-2- base) morpholine -2-yl) methyl) acetamide；
N- (((R) -4- (6- (((R) -2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) morpholine -2-yl) methyl)-2- hydroxyl acetamide；
(S) -2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) Amino)-N- (2- hydroxyethyl)-N- methylacetamide；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- (methylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((6- (4- amino -4- methyl piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) Amino)-N- ((1- (hydroxymethyl) cyclopropyl) methyl)-N- methylacetamide；
2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine - 2- yl) azetidine -3- base) acetamide；
(2S) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl Pyridine -2- base) azetidine -3- base) -3- hydroxypropanamide；
2- ((6- ((S) -3- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((R) -3- hydroxyl pyrrolidine -1- base) -2- oxoethyl) (methyl) ammonia Base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
(2R) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl Pyridine -2- base) azetidine -3- base) -3- hydroxypropanamide；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) Amino)-N- (3- hydroxyl -2,2- dimethyl propyl)-N- methylacetamide；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((S) -3- hydroxyl pyrrolidine -1- base) -2- oxoethyl) (methyl) ammonia Base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((6- (4- amino -4- methyl piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((6- (4- (amino methyl) -4- fluorine resources -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide hydrochloride；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine -2- base) (first Base) amino)-N- (2- amino-ethyl) acetamide hydrochloride；
2- ((3,5- dicyano -4- ethyl -6- (methyl (2- oxo -2- (pyrrolidin-1-yl) ethyl) amino) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- (4- hydroxy piperidine -1- base) -2- oxoethyl) (methyl) amino) pyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (methyl (2- oxo -2- (piperazine -1- base) ethyl) amino) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (methyl (2- morpholino -2- oxoethyl) amino) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
(R) -2- ((6- ((S) -3- (amino methyl) -3- hydroxyl pyrrolidine -1- base) -3,5- dicyano -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- (guanidine radicals oxygroup) pyrrolidin-1-yl) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- amino-N- (2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) (methyl) amino) ethyl) -2- methyl propanamide；
2- ((6- ((2- (2- amino ethoxy) ethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
4- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) piperidin-4-yl) butyramide；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) Amino)-N- (2- amino-ethyl) acetamide；
2- ((6- ((2- (azetidine -1- base) -2- oxoethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((6- ((R) -3- (amino methyl) -3- fluoropyrrolidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- (3- hydroxy azetidine -1- base) -2- oxoethyl) (methyl) ammonia Base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (guanidine radicals oxygroup) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((6- (3- aminoazetidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine；(single stereoisomers)
2- ((3,5- dicyano -4- ethyl -6- ((R) -3- (methylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((3R, 4S) -3- hydroxyl -4- (hydroxymethyl) pyrrolidin-1-yl) -2- oxygen For ethyl) (methyl) amino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
(R) -2- ((6- ((S) -3- (amino methyl) -3- fluoropyrrolidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine -2- base) (first Base) amino)-N- (1,3- dihydroxy propyl- 2- yl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- (oxetanes -3- base amino) piperidin-1-yl) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine -2- base) (first Base) amino)-N, N- bis- (2- hydroxyethyl) acetamide；
2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine - 2- yl) piperidin-4-yl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- ((2- hydroxyethyl) amino) -4- methyl piperidine -1- base) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- (guanidine radicals oxygroup) ethyl) (methyl) amino) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((6- (4- ((2- amino-ethyl) amino) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((S) -2- (hydroxymethyl) morpholino) -2- oxoethyl) (methyl) ammonia Base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((2- ((cis-) -3,4- dihydroxy pyrrolidine -1- base) -2- oxoethyl) (methyl) ammonia Base) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((S) -3- (hydroxymethyl) pyrrolidin-1-yl) -2- oxoethyl) (first Base) amino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((3S, 4S) -3- hydroxyl -4- (hydroxymethyl) pyrrolidin-1-yl) -2- oxygen For ethyl) (methyl) amino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- (neopentyl amino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((R) -3- (hydroxymethyl) pyrrolidin-1-yl) -2- oxoethyl) (first Base) amino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((2- ((3R, 4R) -3,4- dihydroxy pyrrolidine -1- base) -2- oxoethyl) (methyl) ammonia Base) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
(R) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl -3- (hydroxymethyl) pyrrolidin-1-yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
(2S) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl Pyridine -2- base) piperidin-4-yl) propionamide；
2- ((6- (4- (2- amino ethoxy) piperidin-1-yl) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- cyclopropyl -6- (4- ((2- hydroxyethyl) amino) piperidin-1-yl) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) Amino)-N- (1,3- dihydroxy propyl- 2- yl) acetamide；
2- ((3,5- dicyano -6- ((2- ((3R, 5S) -3,5- dihydroxypiperdine -1- base) -2- oxoethyl) (methyl) ammonia Base) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((2- ((3S, 4S) -3,4- dihydroxy pyrrolidine -1- base) -2- oxoethyl) (methyl) ammonia Base) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((2- hydroxyethyl) amino) -4- (hydroxymethyl) piperidin-1-yl) pyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((R) -2- (hydroxymethyl) morpholino) -2- oxoethyl) (methyl) ammonia Base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) Amino)-N- methoxyl acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((3R, 4R) -3- hydroxyl -4- (hydroxymethyl) pyrrolidin-1-yl) -2- oxygen For ethyl) (methyl) amino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) Amino)-N- (3- hydroxypropyl)-N- methylacetamide；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) Amino)-N- ((R) -2,3- dihydroxypropyl) acetamide；
2- ((6- (4- ((2- amino -2- oxoethyl) amino) piperidin-1-yl) -3,5- dicyano -4- cyclopropyl pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) Amino)-N, N- bis- (2- hydroxyethyl) acetamide；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) Amino)-N- (2- hydroxyethyl) acetamide；
2- ((6- ((3- aminopropyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((6- (3- (amino methyl) azetidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) Amino)-N- ((1- (hydroxymethyl) cyclopropyl) methyl) acetamide；
(R) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (2, 4- difluorophenyl) acetamide；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) Amino)-N- (3- (hydroxymethyl) oxetanes -3- base) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (3- (guanidine radicals oxygroup) azetidine -1- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) Amino)-N- (3- hydroxypropyl) acetamide；
2- ((3,5- dicyano -6- (4- (2,3- dihydroxypropyl) -1,4- Diazesuberane -1- base) -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) Amino)-N- hydroxyl acetamide；
3- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine - 2- yl) azetidine -3- base) oxetanes -3- formamide；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (2- fluorobenzene Base) acetamide；
2- ((3,5- dicyano -6- ((S) -3- (cyclopropylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) Amino)-N- (3- hydroxyl -2,2- dimethyl propyl) acetamide；
N- (2- (4H-1,2,4- triazole-4-yl) ethyl) -2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3, 5- dicyano -4- ethylpyridine -2- base) (methyl) amino) acetamide；
N1- (2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (first Base) amino) ethyl) oxamides；
2- ((6- (3- (amino methyl) -3- fluorine azetidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
(R) -2- ((3,5- dicyano -4- ethyl -6- ((R) -3- hydroxyl -3- (hydroxymethyl) pyrrolidin-1-yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((S) -3- ((2,2- bis-fluoro ethyls) amino) piperidin-1-yl) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((6- ((R) -3- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4-methoxypyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((S) -4- hydroxyl isoxazole alkane -2- base) pyridine -2- base) sulfenyl) -2- phenyl second Amide；
(R) -2- ((3,5- dicyano -4- ethyl -6- ((3- hydroxypropyl) (methyl) amino) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -6- ((S) -3- hydroxyl pyrrolidine -1- base) -4-methoxypyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- ethyl -6- (4- (3- methoxyl group azetidine -1- base) piperidin-1-yl) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (3- methoxyl group azetidine -1- base) piperidin-1-yl) pyridine -2- base) Sulfenyl) -2- (4- fluorophenyl) acetamide；
(R) -2- ((3,5- dicyano -4- ethyl -6- ((2- hydroxyethyl) (methyl) amino) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
(R) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (4- Fluorophenyl) acetamide；
(R) -2- ((6- ((R) -3- (amino methyl) -3- hydroxyl pyrrolidine -1- base) -3,5- dicyano -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- (cyclobutyl (methyl) amino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- (4- fluorophenyl) acetamide；With
2- ((3,5- dicyano -4- ethyl -6- (methyl (1- methylpyrrolidin- 3- yl) amino) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
Or its pharmaceutically acceptable salt or prodrug.
7. according to formula (IVbbr) compound:
Wherein:
X41bbrAnd X42bbrIndependently selected from :-CN, methyl, fluorine, chlorine, bromine and iodine；
Y4bbrIt is selected from: S and NH；
R41bbrIt is selected from:
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo, C1-4Alkyl oxy ,- OH、-COOH、-NH2-N(H)C1-4Alkyl ,-N (C1-4Alkyl)2With-CN,
C1-4Alkyl oxy,
Replaced 1-4 C by fluorine1-4Alkyl oxy,
-N(H)C1-4Alkyl,
-N(C1-4Alkyl)2,
-SC1-4Alkyl,
Aryl,
The aryl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-OH ,-NH2With-CN,
C1-4Alkoxy,
- CN,
Oxo,
- OH,
-NO2, and
-NH2,
Heteroaryl,
The heteroaryl replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-OH ,-NH2With-CN,
C1-4Alkoxy,
- CN,
Oxo,
- OH,
-NO2, and
-NH2,
Naphthenic base,
The naphthenic base replaced by 1-4 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-OH ,-NH2With-CN,
C1-4Alkoxy,
- CN,
Oxo,
- OH,
-NO2, and
-NH2；
R43bbrIt is selected from:
C1-4Alkyl,
Phenyl,
The phenyl replaced by 1 or 2 substituent group independently selected from the following: fluorine ,-CH3、-CF3, chlorine ,-C (O) phenyl, pyrrolidines Base ,-P (O) (CH3)2、-C(O)NH2、-S(O)2NHCH3,-OCH2CH2N(CH3)2With-CH2C(O)NH2,
Thienyl,
Piperidyl,
Pyridine, and
The pyridine replaced by 1 or 2 substituent group independently selected from the following: fluorine ,-CH3、-CF3With-OCH3；
R44bbrAnd R45bbrIndependently selected from:
Hydrogen,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: phenyl, morpholino, triazolyl, imidazole radicals, pyrroles Alkyl ,-OC (O) NH2、-OCH2CH2NH2、-ONHC(NH2)NH2、-NHCH2C(CH3)3、-NOCH3、-NHOH、-NHCH2CH2F、-N (CH3)CH2CH2OCH3、-N(CH2CH3)2、-NCH(CH2OH)2、-N(CH2CH2OH)2、-NHCH2CH2OH、-NHCH2CH2NH2、-N (CH3)C(CH3)2CH2OH、-NHCH2CH3、-NHCH2CH2OCH3、-N(CH3)CH2CH2OH、-NHC(O)C(O)NH2、-N(CH3) CH2CH2CH2OH、-N(CH3)CH2CH(OH)CH2OH、-N(CH3)CH2CH2NH2, oxo ,-NHCH2C(CH3)2CH2OH、-OH、- NH2、-NHCH3、-NHCH2CH2CH2OH、-N(CH3)2、-N(CH3)CH2CH3、-NHOC(CH3)2NH2、-N(CH3)CH2Cyclopropyl ,- NHCH2Cyclopropyl ,-NH oxetanyl ,-NCH2CH2Triazole, piperazinyl, piperidyl, pyrazolyl, azepine cycloheptatriene base, Azetidinyl, methoxyl group and cyclopropylamino,
The wherein phenyl, morpholino, triazolyl, imidazole radicals, azepine cycloheptatriene base, azetidinyl, pyrrolidinyl, piperazine Piperazine base, piperidyl, oxetanyl, cyclopropyl and pyrazolyl are optionally replaced by 1-4 substituent groups independently selected from the following: Methyl, fluorine ,-NH2、-N(CH3)2, hydroxymethyl, oxo ,-OH and-CH2NH2,
Naphthenic base,
The naphthenic base replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH,
C1-6Alkyl, and
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl:
Fluorine and chlorine；
Heterocyclylalkyl and
The Heterocyclylalkyl replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, bromine, iodine, oxo ,-OH ,-NH2With-CN,
Aryl,
C1-4Alkoxy,
The C replaced by 1-4 substituent groups independently selected from the following1-4Alkoxy: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- CN,
Oxo,
- OH,
- COOH,
-NO2,
-NH2, and
SO2NH2, or
R44bbrAnd R45bbrNitrogen connected to them and the optionally 1-3 independently selected from O, N and S additional hetero atoms shape together At Heterocyclylalkyl, optionally replaced 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Bromine,
Iodine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, C1-4Alkoxy, oxo, phenyl, cycloalkanes Base, Heterocyclylalkyl, methyl heterocycles alkyl-,-OH ,-NH2、-N(H)C1-5Alkyl, amino-heterocycles alkyl-,-N (C1-5Alkyl)2、- CN、-N(C1-4Alkyl) (CH2OCH3) and-NHC that is replaced by 1 or 2 substituent group independently selected from the following1-4Alkyl: oxo, NH2With-OH,
Aryl,
Naphthenic base,
Heterocyclylalkyl,
The Heterocyclylalkyl replaced by 1-9 substituent groups independently selected from the following: C1-6Alkyl ,-C1-6Alkyl OH, fluorine ,-C1-6Alkane Base NH2, chlorine, bromine, iodine, oxo ,-OH ,-NH2With-CN,
C1-4Alkoxy,
The C replaced by 1-4 substituent groups independently selected from the following1-4Alkoxy: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- CN,
Oxo,
- OH,
-OP(O)(OH)2,
- COOH,
-CONH2,
-NO2,
-NH2,
-N(H)C1-5Alkyl,
- N (H) C replaced by 1-9 substituent groups independently selected from the following1-6
Alkyl: fluorine, chlorine, bromine, iodine, C1-4Alkoxy, oxo, phenyl, naphthenic base, amino C1-4Alkoxy, Heterocyclylalkyl, methyl are miscellaneous Naphthenic base-,-OH ,-NH2、-N(H)C1-4Alkyl ,-N (C1-4Alkyl)2With-CN,
- O oxetanyl,
-ONHC(NH)NH2,
- NH cyclopropyl,
- NH oxetanyl,
-N(C1-5Alkyl)2,
-S(O)2CH2CH3,
S(O)2CH2CH2CH3,
-S(O)2CH3,
-SO2NH2,
-S(O)2Phenyl,
Benzoyl,
Benzylamino,
Propylpyrrolidinyl,
Methylcyclopropyl groups,
Cyclobutylamino,
Cyclobutyl-N (CH3)-,
Piperidyl,
Imidazole radicals,
Morpholinyl,
Morpholinyl methyl,
Methyl piperazine ylmethyl,
Methyl piperazine base,
Pyrrolidinyl,
Pyrrolidinylmethyl,
(methoxypyridylmethyl) amino,
Methylpyrrole alkyl,
Difluoropyrrolidin base,
Alkyl dimethyl pyrrole,
(methylcyclopropylmethyl) amino,
Hydroxymethyl-pyrrolidine base,
Fluoropyrrolidine base,
Fluorophenyl methyl amino,
Piperizinylmethyl,
Oxazolidinyl,
(methy oxetane ylmethyl) amino, (methyl-cyclobutyl methyl) amino,
Oxoimidazolidinyl, and
2- hydroxyethylpiperidine base；
On condition that:
X41bbrAnd X42bbrIt is not all hydrogen, and
R44bbrAnd R45bbrIt is not all hydrogen；
Or its pharmaceutically acceptable salt or prodrug.
8. the compound according to claim 7 represented by following formula (Vbbr):
Wherein:
Y5bbrIt is selected from: S and NH；
R50bbrIt is selected from:
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine and chlorine,
-N(H)C1-4Alkyl,
-N(C1-4Alkyl)2,
-SC1-4Alkyl,
C1-4Alkyl oxy,
Aryl,
The alkyl replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH,
C1-6Alkyl, and
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine and chlorine,
Heteroaryl,
The miscellaneous alkyl replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH,
C1-6Alkyl, and
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine and chlorine,
Naphthenic base,
The naphthenic base replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH,
C1-6Alkyl, and
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine and chlorine；
R51bbrIt is selected from:
-CH3,
Phenyl,
The phenyl replaced by 1 or 2 substituent group independently selected from the following: fluorine ,-CH3、-CF3, chlorine ,-C (O) phenyl, pyrrolidines Base ,-C (O) NH2、-S(O)2NHCH3、-OCH2CH2N(CH3)2With-CH2C(O)NH2,
Thienyl,
Piperidyl,
Pyridine, and
The pyridine replaced by 1 or 2 substituent group independently selected from the following: fluorine ,-CH3、-CF3With-OCH3；
R53bbrAnd R54bbrIndependently selected from:
Hydrogen,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: phenyl, morpholino, triazolyl, imidazole radicals ,- CH2CH2Pyrrolidinyl ,-OC (O) NH2、-OCH2CH2NH2、-ONHC(NH2)NH2、-NHCH2C(CH3)3、-NOCH3、-NHOH、- NHCH2CH2F、-N(CH3)CH2CH2OCH3、-N(CH2CH3)2、-NCH(CH2OH)2、-N(CH2CH2OH)2、NHCH2CH2OH、- NHCH2CH2NH2、-N(CH3)CH2(CH3)2CH2OH、-NHCH2CH3、-NHCH2CH2OCH3、-N(CH3)CH2CH2OH、-NHC(O)C (O)NH2、-N(CH3)CH2CH2CH2OH、-N(CH3)CH2CH(OH)CH2OH、-N(CH3)CH2CH2NH2, oxo ,-NHCH2C (CH3)2CH2OH、-OH、-NH2、-NHCH3、-NHCH2CH2CH2OH、-N(CH3)2、-N(CH3)CH2CH3、-NHOC(CH3)2NH2、- N(CH3)CH2Cyclopropyl ,-NHCH2Cyclopropyl ,-NH oxetanyl ,-NCH2CH2Triazole, piperazinyl, piperidyl, pyrazolyl, Azepine cycloheptatriene base, azetidinyl, methoxyl group and cyclopropylamino,
The wherein phenyl, morpholino, triazolyl, imidazole radicals, azepine cycloheptatriene base, azetidinyl, pyrrolidinyl, piperazine Piperazine base, piperidyl, oxetanyl, cyclopropyl and pyrazolyl are optionally replaced by 1-4 substituent groups independently selected from the following: Methyl, fluorine ,-NH2、-N(CH3)2, hydroxymethyl, oxo ,-OH and-CH2NH2,
Naphthenic base,
The naphthenic base replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH,
C1-6Alkyl, and
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine and chlorine；
Heterocyclylalkyl, and
The Heterocyclylalkyl replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine and chlorine,
C1-4Alkoxy, and
- OH, or
R53bbrAnd R54bbrThe nitrogen connected to them and optionally 1-3 additional hetero atoms independently selected from O, N and S are together Heterocyclylalkyl is formed, is optionally replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, C1-4Alkoxy, oxo, phenyl, cycloalkanes Base, Heterocyclylalkyl, methyl heterocycles alkyl ,-OH ,-NH2、-N(H)C1-5Alkyl, amino-heterocycles alkyl ,-N (C1-5Alkyl)2、-CN、- N(C1-4Alkyl) (CH2OCH3) and-NHC that is replaced by 1 or 2 substituent group independently selected from the following1-4Alkyl: oxo, NH2 With-OH,
Heterocyclylalkyl,
The Heterocyclylalkyl replaced by 1-9 substituent groups independently selected from the following: C1-6Alkyl ,-C1-6Alkyl OH, fluorine ,-C1-6Alkane Base NH2, chlorine, oxo and-OH,
C1-4Alkoxy,
The C replaced by 1-4 substituent groups independently selected from the following1-4Alkoxy: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
- CN,
Oxo,
- OH,
-OP(O)(OH)2,
- COOH,
-CONH2,
-NH2,
-N(H)C1-4Alkyl,
- N (H) C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, C1-4Alkoxy, oxo, benzene Base, naphthenic base, amino C1-4Alkoxy, Heterocyclylalkyl, methyl heterocycles alkyl ,-OH ,-NH2、-N(H)C1-4Alkyl ,-N (C1-4Alkane Base)2With-CN,
- O oxetanyl,
-ONHC(NH)NH2,
- NH cyclopropyl,
- NH oxetanyl,
-N(C1-4Alkyl)2,
-S(O)2CH2CH3,
S(O)2CH2CH2CH3,
-S(O)2CH3,
-S(O)2Phenyl,
Benzoyl,
Benzylamino,
Propylpyrrolidinyl,
Methylcyclopropyl groups,
Cyclobutylamino,
Cyclobutyl-N (CH3)-,
Piperidyl,
Imidazole radicals,
Morpholinyl,
Morpholinyl methyl,
Methyl piperazine ylmethyl,
Methyl piperazine base,
Pyrrolidinyl,
Pyrrolidinylmethyl,
(methoxypyridylmethyl) amino,
Methylpyrrole alkyl,
Difluoropyrrolidin base,
Alkyl dimethyl pyrrole,
(methylcyclopropylmethyl) amino,
Hydroxymethyl-pyrrolidine base,
Fluoropyrrolidine base,
Fluorophenyl methyl amino,
Piperizinylmethyl,
Oxazolidinyl,
(methy oxetane ylmethyl) amino,
(methyl-cyclobutyl methyl) amino,
Oxoimidazolidinyl, and
2- hydroxyethylpiperidine base；
On condition that:
R53bbrAnd R54bbrIt is not all hydrogen；
Or its pharmaceutically acceptable salt or prodrug.
9. being indicated according to the compound of claim 7 or claim 8 by following formula (VIbbr):
Wherein:
R60bbrIt is selected from:
C1-3Alkyl,
The C replaced by 1-6 substituent groups independently selected from the following1-3Alkyl: fluorine and chlorine,
-N(H)C1-3Alkyl,
-N(C1-3Alkyl)2,
-SC1-4Alkyl,
C1-3Alkyl oxy,
Aryl,
The aryl replaced by 1-3 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH, and
C1-3Alkyl,
Heteroaryl,
The heteroaryl replaced by 1-3 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH, and
C1-3Alkyl,
Naphthenic base,
The naphthenic base replaced by 1-3 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH, and
C1-3Alkyl；
R61bbrIt is selected from:
-CH3,
Phenyl,
The phenyl replaced by 1 or 2 substituent group independently selected from the following: fluorine ,-CH3、-CF3, chlorine ,-C (O) phenyl, pyrrolidines Base ,-C (O) NH2、-S(O)2NHCH3、-OCH2CH2N(CH3)2With-CH2C(O)NH2,
Thienyl,
Piperidyl,
Pyridine, and
The pyridine replaced by 1 or 2 substituent group independently selected from the following: fluorine ,-CH3、-CF3With-OCH3；
R63bbrAnd R64bbrIndependently selected from:
Hydrogen,
C1-4Alkyl,
The C replaced by 1-4 substituent groups independently selected from the following1-4Alkyl: phenyl, morpholino, triazolyl, imidazole radicals ,- CH2CH2Pyrrolidinyl ,-OC (O) NH2、-OCH2CH2NH2、-ONHC(NH2)NH2、-NHCH2C(CH3)3、-NOCH3、-NHOH、- NHCH2CH2F、-N(CH3)CH2CH2OCH3、-N(CH2CH3)2、-NCH(CH2OH)2、-N(CH2CH2OH)2、-NHCH2CH2OH、- NHCH2CH2NH2、-N(CH3)CH2(CH3)2CH2OH、-NHCH2CH3、-NHCH2CH2OCH3、-N(CH3)CH2CH2OH、-NHC(O)C (O)NH2、-N(CH3)CH2CH2CH2OH、-N(CH3)CH2CH(OH)CH2OH、-N(CH3)CH2CH2NH2, oxo ,-NHCH2C (CH3)2CH2OH、-OH、-NH2、-NHCH3、-NHCH2CH2CH2OH、-N(CH3)2、-N(CH3)CH2CH3、-NHOC(CH3)2NH2、- N(CH3)CH2Cyclopropyl ,-NHCH2Cyclopropyl ,-NH oxetanyl ,-NCH2CH2Triazole, piperazinyl, piperidyl, pyrazolyl, Azepine cycloheptatriene base, azetidinyl, methoxyl group and cyclopropylamino,
The wherein phenyl, morpholino, triazolyl, imidazole radicals, azepine cycloheptatriene base, azetidinyl, pyrrolidinyl, piperazine Piperazine base, piperidyl, oxetanyl, cyclopropyl and pyrazolyl are optionally replaced by 1-4 substituent groups independently selected from the following: Methyl, fluorine ,-NH2、-N(CH3)2, hydroxymethyl, oxo ,-OH and-CH2NH2,
Naphthenic base,
The naphthenic base replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH, and
C1-6Alkyl,
Heterocyclylalkyl, and
The Heterocyclylalkyl replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH, and
C1-6Alkyl, or
R63bbrAnd R64bbrThe nitrogen connected to them and optionally 1-3 additional hetero atoms for being independently selected from O, N and S shape together At Heterocyclylalkyl, optionally replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
- OH,
-OP(O)(OH)2,
- CN,
C1-6Alkyl,
The C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, C1-4Alkoxy, oxo, phenyl, cycloalkanes Base, Heterocyclylalkyl, methyl heterocycles alkyl ,-OH ,-NH2、-N(H)C1-5Alkyl, amino-heterocycles alkyl ,-N (C1-5Alkyl)2、-CN、- N(C1-4Alkyl) (CH2OCH3) and-NHC that is replaced by 1 or 2 substituent group independently selected from the following1-4Alkyl: oxo, NH2 With-OH,
Heterocyclylalkyl,
The Heterocyclylalkyl replaced by 1-9 substituent groups independently selected from the following: C1-6Alkyl ,-C1-6Alkyl OH, fluorine, chlorine, oxo With-OH,
C1-4Alkoxy,
The C replaced by 1-4 substituent groups independently selected from the following1-4Alkoxy: fluorine, oxo ,-OH ,-COOH ,-NH2With-CN,
Oxo,
-NH2,
-N(H)C1-6Alkyl,
- N (H) C replaced by 1-9 substituent groups independently selected from the following1-6Alkyl: fluorine, chlorine, C1-4Alkoxy, oxo, benzene Base, naphthenic base, amino C1-4Alkoxy, Heterocyclylalkyl, methyl heterocycles alkyl ,-OH ,-NH2、-N(H)C1-4Alkyl ,-N (C1-4Alkane Base)2With-CN,
-ONHC(NH)NH2,
- O oxetanyl,
-ONHC(NH)NH2,
- NH cyclopropyl,
- NH oxetanyl,
-N(C1-4Alkyl)2,
-S(O)2CH2CH3,
S(O)2CH2CH2CH3,
-S(O)2CH3,
-S(O)2Phenyl,
Benzoyl,
Benzylamino,
Propylpyrrolidinyl,
Methylcyclopropyl groups,
Cyclobutylamino,
Cyclobutyl-N (CH3)-,
Piperidyl,
Imidazole radicals,
Morpholinyl,
Morpholinyl methyl,
Methyl piperazine ylmethyl,
Methyl piperazine base,
Pyrrolidinyl,
Pyrrolidinylmethyl,
(methoxypyridylmethyl) amino,
Methylpyrrole alkyl,
Difluoropyrrolidin base,
Alkyl dimethyl pyrrole,
(methylcyclopropylmethyl) amino,
Hydroxymethyl-pyrrolidine base,
Fluoropyrrolidine base,
(fluorophenyl methyl) amino,
Piperizinylmethyl,
Oxazolidinyl,
(methy oxetane ylmethyl) amino,
(methyl-cyclobutyl methyl) amino,
Oxoimidazolidinyl, and
2- hydroxyethylpiperidine base；
On condition that:
R63bbrAnd R64bbrIt is not all hydrogen；
Or its pharmaceutically acceptable salt or prodrug.
10. being indicated according to the compound of any one of claim 7-9 by following formula (Qb):
Wherein:
R70a”It is selected from:
Ethyl,
-OCH3,
-CH2CF3, and
Cyclopropyl；
R71a”It is selected from:
Phenyl,
The phenyl replaced by 1 or 2 substituent group independently selected from the following: fluorine ,-CH3、-CF3And chlorine,
Pyridine, and
The pyridine replaced by 1 or 2 substituent group independently selected from the following: fluorine ,-CH3、-CF3With-OCH3；With
R72a”And R73a”Independently selected from:
Hydrogen,
C1-4Alkyl,
The C replaced by 1-4 substituent groups independently selected from the following1-4Alkyl: phenyl, morpholino, triazolyl, imidazole radicals ,- CH2CH2Pyrrolidinyl ,-OC (O) NH2、-OCH2CH2NH2、-ONHC(NH2)NH2、-NHCH2C(CH3)3、-NOCH3、-NHOH、- NHCH2CH2F、-N(CH3)CH2CH2OCH3、-N(CH2CH3)2、-NCH(CH2OH)2、-N(CH2CH2OH)2、-NHCH2CH2OH、- NHCH2CH2NH2、-N(CH3)CH2(CH3)2CH2OH、-NHCH2CH3、-NHCH2CH2OCH3、-N(CH3)CH2CH2OH、-NHC(O)C (O)NH2、-N(CH3)CH2CH2CH2OH、-N(CH3)CH2CH(OH)CH2OH、-N(CH3)CH2CH2NH2, oxo ,-NHCH2C (CH3)2CH2OH、-OH、-NH2、-NHCH3、-NHCH2CH2CH2OH、-N(CH3)2、-N(CH3)CH2CH3、-NHOC(CH3)2NH2、- N(CH3)CH2Cyclopropyl ,-NHCH2Cyclopropyl ,-NH oxetanyl ,-NCH2CH2Triazole, piperazinyl, piperidyl, pyrazolyl, Azepine cycloheptatriene base, azetidinyl, methoxyl group and cyclopropylamino,
The wherein phenyl, morpholino, triazolyl, imidazole radicals, azepine cycloheptatriene base, azetidinyl, pyrrolidinyl, piperazine Piperazine base, piperidyl, oxetanyl, cyclopropyl and pyrazolyl are optionally replaced by 1-4 substituent groups independently selected from the following: Methyl, fluorine ,-NH2、-N(CH3)2, hydroxymethyl, oxo ,-OH and-CH2NH2,
Cyclobutyl,
Aminocyclobutyl,
Tetrahydrofuran,
5- oxa- -2- azaspiro [3.4] octane, and
8- azabicyclo [3.2.1] octane, or
R72a”And R73a”The nitrogen connected to them and optionally 1-3 additional hetero atoms independently selected from O, N and S are together Form Heterocyclylalkyl selected from the following:
Pyrrolidinyl,
Pyrrolo- [3,4-c] pyrazolyl,
Piperidyl,
Isosorbide-5-Nitrae-Diazesuberane base,
Piperazinyl,
6,7- dihydros-triazol [4,5-c] pyridyl group,
2,9- diaza spiros [5.5] undecyl,
2,8- diaza spiros [4.5] decyl,
Octahydro -1H- pyrrolo- [1,2a] [Isosorbide-5-Nitrae] diaza cycloheptatriene base,
Oxa--diaza spiro [4.5] decyl,
Oxazolyl,
Morpholinyl,
1- oxa- -6- azaspiro [3.4] octyl,
2- oxa- -6- azaspiro [3.4] octyl,
1,7- diaza spiro [3.5] nonyl,
2,7- diaza spiros [3.5] nonyl,
2,6- diaza spiros [3.4] octyl,
Azetidinyl,
Hexahydropyrrolo simultaneously [3,4-b] oxazines base,
Dihydro phthalazinyl,
Diazabicyclo heptane base,
1,8- diaza spiro [4.5] decyl, and
5- oxa- -2- azaspiro [3.4] octyl,
These groups are all optionally replaced by 1-5 substituent groups independently selected from the following:
Fluorine,
Chlorine,
Oxo,
- OH,
-OP(O)(OH)2,
- CN,
-CH3,
-CH2OH,
Methoxyl group,
-CH2CH3,
-C(O)CH3,
-C(O)NH2,
-OCH2CH2OH,
-OCH2CH2NH2,
-ONHC(NH)NH2,
-OC(O)NH2,
- O oxetanyl,
-CH2CH2OH,
-CH2CH2CH2OH,
-CH2CH2CH3,
-CH2CH2OCH3,
-CH2CH(OH)CH3,
-CH2CH(OH)CH2OH,
-CH2C(O)OCH3,
-CH2C(O)NH2,
-C(O)CH(CH3)2,
-CH2CH2N(CH3)2,
-CH2CH2NHCH2CH3,
-CH2CH2CH2N(CH3)2,
-CH2CH2NHCH2C(CH3)3,
-CH2CH2N(CH3)CH2OCH3,
-C(CH3)2CH2OH,
-CH2C(CH3)2OH,
-CH2C(CH3)2OCH3,
-C(O)CH2OH,
-CH2Isothiazolyl,
-CH2Thiazolyl,
-CH2Pyrazolyl,
-CH2Imidazole radicals,
-CH2Pyridyl group,
-CH2Oxazolyl,
-CH2Pyrrole radicals,
-CH2Isoxazolyl,
-CH2Furyl,
-CH2CH2Morpholinyl,
-CH2CH2Pyrrolidinyl,
-CH2CH2Pyrrolidinyl CH3,
-CH2CH2CH2Pyrrolidinyl,
- C (O) phenyl,
- C (O) C (THP trtrahydropyranyl) NH2,
-NH2,
-NHCH3,
-N(CH3)2,
-NHC(O)CH3,
-NHCH2CHF2,
-NHCH2C(CH3)3,
-NHCH2CH(CH3)2,
-NHCH2CH2OCH3,
-NHCH2CH2OH,
-NHCH2CH2NH2,
-NHCH2C(O)OH,
-NHC(O)CH2NH2,
-NHC(O)CH2CH2CH2NH2,
-NHCH2C(O)NH2,
-NHCH2C(OH)(CH3)2,
-NHC(O)CH(CH3)NH2,
-NHC(O)OCH(CH3)NH2,
-NHC(O)CH(CH3)2,
-NHC(O)C(CH3)2NH2,
-NHC(O)CH2OH,
-NHC(O)CH(CH2OH)NH2,
- NHC (O) (oxetanyl) NH2,
-NHC(O)OC(CH3)3,
-NHC(CH3)2C(O)OCH3,
- NH cyclopropyl,
- NH oxetanyl,
-CH2NH2,
-CH2CH2NH2,
-CH2CH2CH2NH2,
-CH2NHCH2C(CH3)3,
-CH2NHC(O)C(CH3)3,
-CH2NHC(O)CH2NH2,
-CH2NHC(O)CH2OH,
-CH2N(CH3)2,
-CH2NHCH3,
-CH2N(CH2CH3)2,
-CH2CH2N(CH3)2,
-S(O)2CH2CH3,
-S(O)2CH2CH2CH3,
-S(O)2Phenyl,
-S(O)2CH3,
Benzoyl,
Benzylamino,
Propylpyrrolidinyl,
Methylcyclopropyl groups,
Cyclobutylamino,
Cyclobutyl-N (CH3)-,
Piperidyl,
Imidazole radicals,
Morpholinyl,
Morpholinyl methyl,
Methyl piperazine ylmethyl,
Methyl piperazine base,
Pyrrolidinyl,
Pyrrolidinylmethyl,
(methoxypyridylmethyl) amino,
Methylpyrrole alkyl,
Difluoropyrrolidin base,
Alkyl dimethyl pyrrole,
(methylcyclopropylmethyl) amino,
Hydroxymethyl-pyrrolidine base,
Fluoropyrrolidine base,
(fluorophenyl methyl) amino,
Piperizinylmethyl,
Oxazolidinyl,
(methy oxetane ylmethyl) amino,
(methyl-cyclobutyl methyl) amino,
Oxoimidazolidinyl, and
2- hydroxyethylpiperidine base；
On condition that:
R72a”And R73a”It is not all hydrogen；
Or its pharmaceutically acceptable salt or prodrug.
11. compound according to claim 7, is selected from:
2- { [3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base] sulfanyl } -2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- { [3,5- dicyano -4- cyclopropyl -6- (4- ethyl -1,4- Diazesuberane -1- base) pyridine -2- base] sulfane Base } -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- propyl -1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- { [3,5- dicyano -4- ethyl -6- (4- ethyl -1,4- Diazesuberane -1- base) pyridine -2- base] sulfanyl } - 2- phenyl-acetamides；
2- { [3,5- dicyano -4- ethyl -6- (5- oxo -1,4- Diazesuberane -1- base) pyridine -2- base] sulfanyl } - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- morpholino pyridine -2- base) sulfenyl) -2- (pyridin-4-yl) acetamide；
2- { [3,5- dicyano -4- ethyl -6- (4- methyl -3- oxypiperazin -1- base) pyridine -2- base] sulfanyl } -2- (pyrrole Pyridine -4- base) acetamide；
2- [(3,5- dicyano -4- ethyl -6- { methyl [2- (morpholine -4- base) ethyl] amino } pyridine -2- base) sulfanyl] -2- Phenyl-acetamides；
2- { [3,5- dicyano -4- ethyl -6- (4- propylpiperazine -1- base) pyridine -2- base] sulfanyl } -2- phenyl-acetamides；
2- ({ 3,5- dicyano -4- ethyl -6- [4- (piperidin-4-yl) piperazine -1- base] pyridine -2- base } sulfanyl) -2- phenyl Acetamide；
2- ({ 3,5- dicyano -4- cyclopropyl -6- [3- (hydroxymethyl) piperazine -1- base] pyridine -2- base } sulfanyl) -2- phenyl Acetamide；
2- { [3,5- dicyano -4- cyclopropyl -6- (3- oxypiperazin -1- base) pyridine -2- base] sulfanyl } -2- phenylacetyl Amine；
2- ({ 3,5- dicyano -4- cyclopropyl -6- [4- (morpholine -4- base) piperidin-1-yl] pyridine -2- base } sulfanyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- (2,8- diaza spiro [4.5] decyl- 8- yl) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- cyclopropyl -6- (3- (dimethylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- cyclopropyl -6- (3- methylpiperazine-1-yl) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (2- (hydroxymethyl) morpholino) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- cyclopropyl -6- (2,6- thebaine generation) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (3- (dimethylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((6- (4- (amino methyl) -4- hydroxy piperidine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (3- (methylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((6- (3- amino piperidine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (dimethylamino) pyridine -2- base) sulfenyl) -2- (pyridin-4-yl) acetyl Amine；
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (pyridin-4-yl) acetamide；
2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (4- (dimethylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- cyclopropyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- (pyridin-4-yl) acetamide；
2- ((3,5- dicyano -4- cyclopropyl -6- (1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (pyridine - 4- yl) acetamide；
2- ((3,5- dicyano -4- cyclopropyl -6- ((R) -3- hydroxy piperidine -1- base) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- (3,5- dicyano -4- cyclopropyl -6- ((S) -3- hydroxy piperidine -1- base) pyridine -2- base sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- cyclopropyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (pyridine - 4- yl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- ethyl piperazidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (1- oxa- -6- azaspiro [3.4] octyl- 6- yl) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((6- (4- (3- aminopropyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- ethyl -6- (1,7- diaza spiro [3.5] nonyl- 1- yl) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- cyclopropyl -6- (4- (pyrrolidin-1-yl methyl) piperidin-1-yl) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
(R) -2- ((3,5- dicyano -6- (1,4- Diazesuberane -1- base) -4- ethylpyridine -2- base) amino) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- cyclopropyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- (2,7- diaza spiro [3.5] nonyl- 7- yl) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- ethyl -6- (2,6- diaza spiro [3.4] octyl- 6- yl) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- cyclopropyl -6- (1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) propionamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (2- oxo-imidazole alkane -1- base) piperidin-1-yl) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- hydroxy piperidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- (3- oxypiperazin -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- methoxy ethyl) (methyl) amino) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- ethyl -6- (3- methoxyl group azetidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- ethyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- morpholino pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- [[6- (azetidine -1- base) -3,5- dicyano -4- ethyl -2- pyridyl group] sulfanyl] -2- phenvl-acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- oxo-piperidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (1'- (2- hydroxyethyl)-[4,4'- joins piperidines] -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((3S, 5R) -3,5- lupetazin -1- base) -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((6- (8- azabicyclo [3.2.1] oct-3-yl (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (2- (hydroxymethyl) morpholino) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
(R) -2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
(R) -2- [(3,5- dicyano -4- ethyl -6- morpholino -2- pyridyl group) sulfanyl] -2- phenvl-acetamide；
2- { [3,5- dicyano -4- ethyl -6- (5- methyl-1,4- Diazesuberane -1- base) pyridine -2- base] sulfanyl } - 2- phenyl-acetamides；
2- ({ 3,5- dicyano -4- ethyl -6- [4- (2- methoxy ethyl) -1,4- Diazesuberane -1- base] pyridine -2- Base } sulfanyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxypropyl) -1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- [4- (6- { [carbamoyl (phenyl) methyl] sulfanyl } -3,5- dicyano -4- ethylpyridine -2- base) -1,4- two Azepan -1- base] methyl acetate；
2- { [3,5- dicyano -4- cyclopropyl -6- (4- methyl -5- oxo -1,4- Diazesuberane -1- base) pyridine -2- base] Sulfanyl } -2- phenyl-acetamides；
2- { [3,5- dicyano -4- cyclopropyl -6- (5- oxo -1,4- Diazesuberane -1- base) pyridine -2- base] sulfane Base } -2- phenyl-acetamides；
2- { [3,5- dicyano -4- ethyl -6- (4- methyl -5- oxo -1,4- Diazesuberane -1- base) pyridine -2- base] sulphur Alkyl } -2- phenyl-acetamides；
2- { [3,5- dicyano -6- (1,4- Diazesuberane -1- base) -4- ethylpyridine -2- base] sulfanyl } -2- phenyl second Amide；
2- ({ 3,5- dicyano -6- [4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base] -4- (2,2,2- trifluoro second Base) pyridine -2- base } sulfanyl) -2- phenyl-acetamides；
(2R) -2- ({ 3,5- dicyano -4- ethyl -6- [4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base] pyridine - 2- yl } amino) -2- phenyl-acetamides；
2- ({ 6- [(3S) -3- amino-pyrrolidine -1- base] -3,5- dicyano -4- cyclopropyl pyridine -2- base } sulfanyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- (2,9- diaza spiro [5.5] hendecane -9- base) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (hexahydro -1H- pyrrolo- [1,2-a] [1,4] diazacyclo heptantriene -2 (3H) - Base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (2- methyl -2,9- diaza spiro [5.5] hendecane -9- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (2- (Cvclopropvlmethvl) -2,9- diaza spiro [5.5] hendecane -9- base) -4- ethyl pyrrole Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- (3- (dimethylamino) propyl) piperazine -1- base) -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-3-yl) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((6- ([4,4'- joins piperidines] -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((6- (4- (2- amino-ethyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((6- (4- (3- aminopropyl) piperazine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- cyclopropyl -6- (4- ((4- methylpiperazine-1-yl) methyl) piperidin-1-yl) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((6- (4- Acetylpiperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- cyclopropyl -6- (dimethylamino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- (4- chlorphenyl) -2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxyethyl) piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- [(3,5- dicyano -4- cyclopropyl -6- morpholino -2- pyridyl group) sulfanyl] -2- phenvl-acetamide；
2- ((6- (4- benzoyl-piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- ((5S, 6S) -6- hydroxyl -1- (methyl sulphonyl) -1,8- diaza spiro [4.5] Decyl- 8- yl) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4,4- difluoropiperdin -1- base) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
(R) -2- ((3,5- dicyano -4- ethyl -6- ((R) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- (furans -2- base) -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((6- (4- amino -4- methyl piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) piperidin-4-yl) acetamide；
(2S) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) propionamide；
2- ((6- (4- (3- amino oxetanes -3- carbonyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
4- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) piperidin-4-yl) tetrahydro -2H- pyrans -4- formamide；
2- ((6- (4- (4- amino tetrahydro -2H- pyrans -4- carbonyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base) -4-methoxypyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((6- ((2- amino-ethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((6- ((2- amino -2- oxoethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (3- hydroxy azetidine -1- base) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- (3,5- dicyano -4- ethyl -6- ((2- hydroxyethyl) (methyl) amino) pyridine -2- base sulfenyl) -2- phenylacetyl Amine；
2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) piperidin-4-yl) -2- methyl propanamide；
2- ((6- (4- (2- amino ethoxy) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl Acetamide；
Biphosphate 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) Pyrrolidin-3-yl ester；
Biphosphate 2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) (methyl) amino) ethyl ester；
Biphosphate 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) Azetidine -3- base ester；
(2S) -2- amino -3 Methylbutanoic acid 2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyan Base -4- ethylpyridine -2- base) piperidin-4-yl) oxygroup) ethyl ester；
Biphosphate 2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) piperidin-4-yl) oxygroup) ethyl ester；
Biphosphate 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) Piperidin-4-yl ester；
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (piperidin-4-yl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (sulfonyl propyl base) piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- ethyl -6- (4- (phenyl sulfonyl) piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- ethyl -6- ((R) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- (2- oxa- -6- azaspiro [3.4] octyl- 6- yl) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
(R) -2- ((3,5- dicyano -4- ethyl -6- (4- ethyl -1,4- Diazesuberane -1- base) pyridine -2- base) ammonia Base) -2- phenyl-acetamides；
(R) -2- ((3,5- dicyano -4- ethyl -6- (4- (3- (pyrrolidin-1-yl) propyl) -1,4- Diazesuberane -1- Base) pyridine -2- base) amino) -2- phenyl-acetamides；
2- (3,5- dicyano -4- cyclopropyl -6- (3- hydroxy piperidine -1- base) pyridine -2- base sulfenyl) -2- phenyl-acetamides；
2- ((the chloro- 4- ethyl -6- of 3,5- bis- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -6- (1,1- sulfur dioxide morpholino) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (methyl (2- (piperazine -1- base) ethyl) amino) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
(R) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((6- ((2- (4- (amino methyl) -4- hydroxy piperidine -1- base) ethyl) (methyl) amino) -3,5- dicyano -4- second Yl pyridines -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((4- cyano -3- (1,4- Diazesuberane -1- base) -6,7- dihydro -5H- cyclopenta [c] pyridine -1- base) Sulfenyl) -2- phenyl-acetamides；
2- ((6- (4- (1H- imidazoles -1- base) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (pyridin-4-yl methyl) piperazine -1- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -6- (2- (dimethylamino) ethyoxyl) -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine -2- base) piperazine Pyridine -3- base) amino) acetic acid；
2- ((3,5- dicyano -4- ethyl -6- (4- (oxazole -2- ylmethyl) piperazine -1- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((6- (4- ((1H- pyrroles -2- base) methyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -6- (- 2 (1H)-yl of 3,4- dihydro -2,7- benzodiazine) -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (pyridine -3- Base) acetamide；
2- ((6- (4- ((1H- pyrroles -3- base) methyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (isoxazole -3- ylmethyl) piperazine -1- base) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (oxazole -5- ylmethyl) piperazine -1- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (isoxazole -4- ylmethyl) piperazine -1- base) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
3- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) piperidin-4-yl) oxetanes -3- formamide；
2- ((6- (4- ((1H- pyrazoles -4- base) methyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((6- (4- ((1H- imidazoles -5- base) methyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (1- hydroxy-2-methyl propyl- 2- yl) piperazine -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((6- (4- ((1H- imidazoles -2- base) methyl) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -6- (dimethylamino) -4-methoxypyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (dimethylamino) -4- ethoxy pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyoxyl -6- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxy-2-methyl propyl) -1,4- Diazesuberane -1- base) pyrrole Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (thiazole -5- ylmethyl) piperazine -1- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- (4- fluorophenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (isothiazole -4- ylmethyl) piperazine -1- base) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (4- fluorophenyl) acetamide；
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (5- fluorine pyridine -2- base) acetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- (4- (furans -3- ylmethyl) piperazine -1- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((2- morpholinoethyl) sulfenyl) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- methyl-1,4- Diazesuberane -1- base) -4- (methylsulfany) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((the chloro- 4- ethyl -6- of 3,5- bis- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (hexahydropyrrolo simultaneously [3,4-b] [1,4] oxazines -6 (2H)-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (5- picoline -2- base) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (6- fluorine pyridine -2- base) acetamide；
2- ((3,5- dicyano -6- (4- (dimethylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- (4- fluorine Phenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (4- picoline -2- base) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (3-Methoxy Pyridine -2- base) acetamide；
2- ((3,5- dicyano -6- (4- (dimethylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- (2,4- Difluorophenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- (5- fluorine Pyridine -2- base) acetamide；
2- ((3,5- dicyano -4- ethyoxyl -6- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) propionamide；
2- ((3,5- dicyano -6- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base) -4- propoxyl group pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (4-methoxypyridine -2- base) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (2- methyl -2,8- diaza spiro [4.5] decyl- 8- yl) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- (dimethylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- (3,4- Difluorophenyl) acetamide；
1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidines -4- Formamide；
2- ((3,5- dicyano -6- ((2- (dimethylamino) ethyl) sulfenyl) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -6- ((3S, 4R) -3,4- dihydroxy pyrrolidine -1- base) -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (3- fluorine pyridine -2- base) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (5- methoxypyridine -2- base) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (1- hydroxy-2-methyl propyl- 2- yl) piperazine -1- base) pyridine -2- base) sulphur Base) -2- (4- fluorophenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (3- (trifluoromethyl) phenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxyl-oxethyl) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (2- fluorine pyridin-3-yl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (6- fluorine pyridin-3-yl) acetamide；
3- ((6- (2- amino -2- oxo -1- phenylethyl sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) ammonia Base) propionamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (oxetanes -3- base oxygroup) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- ((2,2- bis-fluoro ethyls) amino) -4- methyl piperidine -1- base) -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (4- (trifluoromethyl) phenyl) acetamide；
2- ((6- (4- aminopiperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((6- ((2- amino -2- oxoethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- ethyl -6- (pyrrolo- [3,4-c] pyrazoles -5 (1H, 4H, 6H)-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (5- methoxypyridine -2- base) Acetamide；
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (5- picoline -2- base) second Amide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (2- fluorine pyridin-4-yl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- hydroxyl -4- (hydroxymethyl) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (2- oxo -3- oxa- -1,8- diaza spiro [4.5] decyl- 8- yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((6- (4- amino -4- (hydroxymethyl) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((6- (4- (amino methyl) -4- hydroxy piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- (3- benzoylphenyl) -2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxyethyl) -1,4- diaza cycloheptyl Alkane -1- base) pyridine -2- base) sulfenyl) acetamide；
2- (4- benzoylphenyl) -2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxyethyl) -1,4- diaza cycloheptyl Alkane -1- base) pyridine -2- base) sulfenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (2- picoline -4- base) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (3- (pyrrolidin-1-yl) phenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (3- fluorine pyridin-4-yl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (2,5- difluoro pyridine -4- base) acetamide；
2- ((3,5- dicyano -6- (4- (2,5- dioxo alkyl imidazole -1- base) piperidin-1-yl) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
4- amino -1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) Piperidines -4- formamide；
2- ((3,5- dicyano -6- (4- (2,5- dioxo pyrrolidin -1- base) piperidin-1-yl) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides (isomers 1)；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides (isomers 2)；
2- ((3,5- dicyano -4- ethyl -6- (2- oxo -1- oxa- -3,8- diaza spiro [4.5] decyl- 8- yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) -4- hydroxyl Piperidines -4- formamide；
Carbamic acid 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) Azetidine -3- base ester；
2- ((3,5- dicyano -6- (4- (2,4- dioxo oxazolidine -3- base) piperidin-1-yl) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
3- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) Amino) -2- hydroxy-2-methyl propionamide；
2- ((3,5- dicyano -4- ethyl -6- (3- (hydroxymethyl) azetidine -1- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- (3,5- dicyano -4- ethyl -6- (piperazine -1- base) pyridine -2- base sulfenyl) -2- (thiene-3-yl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (5- picoline -3- base) acetamide；
2- ((6- (4- (3- amino -2- oxo-pyrrolidine -1- base) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
(2S) -2- amino -3 Methylbutanoic acid 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- Ethylpyridine -2- base) piperidin-4-yl ester；
(2S) -2- amino -3 Methylbutanoic acid 2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano - 4- ethylpyridine -2- base) (methyl) amino) ethyl ester；
2,2'- ((3,5- dicyano -4- ethylpyridine -2,6- diyl) bis- (sulfane diyls)) bis- (2- phenyl-acetamides)；
(2S) -2- amino -3 Methylbutanoic acid (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano - 4- ethylpyridine -2- base) azetidine -3- base) methyl ester；
2- ((6- (3- aminoazetidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- picoline -2- base) sulfenyl) -2- phenyl-acetamides；
N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidines - 4- yl) -2- hydroxyl acetamide；
N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) azepine Cyclobutane -3- base) -2- hydroxyl acetamide；
2- ((3- cyano -4- ethyl -5- methyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (5- methyl -2,5- diazabicyclo [2.2.1] hept- 2- yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (2- (pyrrolidin-1-yl) ethyl) piperazine -1- base) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides -2-d；
(R) -2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides -2-d；
2- ((6- (4- (4- benzoyl bromide) piperazine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxyethyl) -1,4- Diazesuberane -1- base) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- cyano piperidine -1- base) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
(S) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((6- (4- amino -4- methyl piperidine -1- base) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (pyridine -2- Base) acetamide；
2- ((3,5- bis- chloro- 4- ethyl -6- (piperazine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
(1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperidines -4- Base) t-butyl carbamate；
2- ((6- (3- (2- amino -2- oxoethyl) azetidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
(2R) -2- amino -3 Methylbutanoic acid 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- Ethylpyridine -2- base) azetidine -3- base ester；
2- ((3,5- dicyano -4- ethyl -6- (methyl ((5- oxo -4,5- dihydro -1H-1,2,4- triazole -3- base) methyl) ammonia Base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((6- (((4H-1,2,4- triazole -3- base) methyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyoxyl -6- picoline -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4,6- parvoline -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((6- ((2- (4H-1,2,4- triazole-4-yl) ethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((6- (((1H- pyrazole-3-yl) methyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -6- (6,7- dihydro -1H- [1,2,3] triazol [4,5-c] pyridine -5 (4H)-yl) -4- ethyl pyrrole Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((6- (((1H- imidazoles -2- base) methyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((6- (((1H- imidazoles -5- base) methyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
(2R) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) propionamide；
4- (2- amino -1- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- Base) sulfenyl) -2- oxoethyl) benzamide；
2- ((3,5- dicyano -4- cyclopropyl -6- (3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- (3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
(2R) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl Pyridine -2- base) piperidin-4-yl) propionamide；
2- ((6- ((2- amino-ethyl) (methyl) amino) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine - 2- yl) piperidin-4-yl) -2- methyl propanamide；
4- (2- amino -1- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- oxoethyl) Benzamide；
2- (6- (4- amino piperidine -1- base) -3- cyano -4- ethyl -5- picoline -2- base sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- (4- (N- Methylsulfamoyl) phenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (the fluoro- 1,4- Diazesuberane -1- base of 6-) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((6- (4- amino -3,3- difluoropiperdin -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl Acetamide；
(1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) -3,3- two Fluorine resources -4- base) t-butyl carbamate；
2- ((3,5- dicyano -4- cyclopropyl -6- ((2- hydroxyethyl) (methyl) amino) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- cyclopropyl -6- (3- hydroxy azetidine -1- base) pyridine -2- base) sulfenyl) -2- phenyl second Amide；
1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) pyrrolidines - 3- formamide；
2- ((6- ((3- aminopropyl) (methyl) amino) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- cyclopropyl -6- ((2- (3- hydroxy azetidine -1- base) -2- oxoethyl) (methyl) ammonia Base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((6- (4- ((2- amino -2- oxoethyl) amino) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((6- ((2- amino -2- oxoethyl) (methyl) amino) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
Carbamic acid 2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine -2- Base) (methyl) amino) ethyl ester；
(2R) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) -3- hydroxypropanamide；
(2S) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidin-4-yl) -3- hydroxypropanamide；
2- (4- (2- amino -2- oxoethyl) phenyl) -2- (3,5- dicyano -4- ethyl -6- (4- methyl-1,4- diazacyclo Heptane -1- base) pyridine -2- base sulfenyl) acetamide；
2- (4- (2- amino -2- oxoethyl) phenyl) -2- (3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- Base sulfenyl) acetamide；
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (4- (N- Methylsulfamoyl) Phenyl) acetamide；
2- ((3,5- dicyano -6- (dimethylamino-d6) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
(R) -2- ((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
(R) -2- ((3,5- dicyano -6- (4- (dimethylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- (3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base sulfenyl) -2- (3- (2- (dimethylamino) second Oxygroup) phenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (neopentyl amino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- (4- fluorine Phenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (the fluoro- 4- of 3- (neopentyl amino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- (4- (trifluoromethyl) Phenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
(R) -2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((6- ((2- amino -2- oxoethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides；(single enantiomer)；
Biphosphate (3S) -1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) pyrrolidin-3-yl ester；
Biphosphate (3R) -1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) pyrrolidin-3-yl ester；
Biphosphate (S) -1- (6- (((S) -2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) pyrrolidin-3-yl ester；
Biphosphate (S) -1- (6- (((R) -2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) pyrrolidin-3-yl ester；
2- ((3,5- dicyano -6- (dimethylamino) -4- ethylpyridine -2- base) sulfenyl) -2- (3- (solutions of dimethyl phosphoryl base) benzene Base) acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (3- (diformazan Base phosphoryl) phenyl) acetamide；
Biphosphate (R) -2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) (methyl) amino) ethyl ester；
(R) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (4- Methoxyphenyl) acetamide；
(R) -2- (4- chlorphenyl) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- Base) sulfenyl) acetamide；
(R) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (4- Fluorophenyl) acetamide；
Biphosphate (S) -1- (6- (((R) -2- amino -1- (4- fluorophenyl) -2- oxoethyl) sulfenyl) -3,5- dicyano -4- Ethylpyridine -2- base) pyrrolidin-3-yl ester；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (4- fluorobenzene Base) acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (2,6- bis- Fluorophenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (2,3- bis- Fluorophenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (2,4- bis- Fluorophenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- ((S) -2- (hydroxymethyl) pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((2- hydroxyethyl) (methyl) amino) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((2- hydroxy-2-methyl propyl) (methyl) amino) piperidin-1-yl) pyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-1-yl methyl) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((2- methoxyl group -2- methyl-propyl) amino) piperidin-1-yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((2- hydroxy-2-methyl propyl) amino) piperidin-1-yl) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- (Cyclobutylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- ethyl -6- (4- (((3- methy oxetane -3- base) methyl) amino) piperidin-1-yl) Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (4- methylpiperazine-1-yl) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((R) -2- methylpyrrolidin- 1- yl) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- ((2R, 5S) -2,5- dimethyl pyrrolidine -1- base) piperidin-1-yl) -4- ethylpyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((S) -2- methylpyrrolidin- 1- yl) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- (cyclobutyl (methyl) amino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- (6- (4- (benzylamino) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- (4- (((6- methoxypyridine -2- base) methyl) amino) piperidin-1-yl) pyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((S) -3- fluoropyrrolidine -1- base) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (methyl (2- ((R) -2- methylpyrrolidin- 1- yl) ethyl) amino) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((R) -3- fluoropyrrolidine -1- base) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- ((2S, 5S) -2,5- dimethyl pyrrolidine -1- base) piperidin-1-yl) -4- ethylpyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (methyl (2- ((S) -2- methylpyrrolidin- 1- yl) ethyl) amino) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((R) -2- (hydroxymethyl) pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- (dimethylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- (4- fluorine Phenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (((1- methyl-cyclobutyl) methyl) amino) piperidin-1-yl) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (((6- methoxypyridine -3- base) methyl) amino) piperidin-1-yl) pyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- (3,5- dicyano -4- ethyl -6- ((2- (ethylamino) ethyl) (methyl) amino) pyridine -2- base sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- ((4- methylpiperazine-1-yl) methyl) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (methyl (2- (methylamino) ethyl) amino) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -6- (4- ((2R, 5R) -2,5- dimethyl pyrrolidine -1- base) piperidin-1-yl) -4- ethylpyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (((1- methylcyclopropyl groups) methyl) amino) piperidin-1-yl) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((4- luorobenzyl) amino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((S) -2- (hydroxymethyl) pyrrolidin-1-yl) ethyl) (methyl) amino) Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- (3,5- dicyano -6- ((2- ((2S, 5R) -2,5- dimethyl pyrrolidine -1- base) ethyl) (methyl) amino) -4- second Yl pyridines -2- base sulfenyl) -2- phenyl-acetamides；
2- ((6- ((2- (azepan -1- base) ethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (methyl (2- (piperidin-1-yl) ethyl) amino) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((R) -2- (hydroxymethyl) pyrrolidin-1-yl) ethyl) (methyl) amino) Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- (3,5- dicyano -4- ethyl -6- ((2- (ethyl (methyl) amino) ethyl) (methyl) amino) pyridine -2- base sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((2- ((2R, 5R) -2,5- dimethyl pyrrolidine -1- base) ethyl) (methyl) amino) -4- second Yl pyridines -2- base) sulfenyl) -2- phenyl-acetamides；
2- (3,5- dicyano -4- ethyl -6- ((2- ((S) -3- hydroxyl pyrrolidine -1- base) ethyl) (methyl) amino) pyridine -2- Base sulfenyl) -2- phenyl-acetamides；
2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperazine Pyridine -4- base) amino) -2 Methylpropionic acid methyl esters；
2- ((3,5- dicyano -4- ethyl -6- (methyl (2- (neopentyl amino) ethyl) amino) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- (3,5- dicyano -4- ethyl -6- (methyl (2- (1- methylcyclopropyl groups amino) ethyl) amino) pyridine -2- base sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((2- ((2S, 5S) -2,5- dimethyl pyrrolidine -1- base) ethyl) (methyl) amino) -4- second Yl pyridines -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((2- methoxy ethyl) amino) ethyl) (methyl) amino) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((2- methoxyl group -2- methyl-propyl) (methyl) amino) piperidin-1-yl) pyrrole Pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((2- (dimethylamino) ethyl) (methyl) amino) -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- (3,5- dicyano -4- ethyl -6- ((2- ((R) -3- hydroxyl pyrrolidine -1- base) ethyl) (methyl) amino) pyridine -2- Base sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((2- fluoro ethyl) amino) ethyl) (methyl) amino) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- (3,3- difluoropyrrolidin -1- base) piperidin-1-yl) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) piperazine Pyridine -4- base) amino) acetic acid；
2- ((6- ((3- Aminocyclobutyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl Acetamide；
(R) -2- (3,5- dicyano -4- ethyl -6- (methyl ((R)-tetrahydrofuran -3- base) amino) pyridine -2- base sulfenyl) -2- Phenyl-acetamides；
(S) -2- (3,5- dicyano -4- ethyl -6- (methyl ((R)-tetrahydrofuran -3- base) amino) pyridine -2- base sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- morpholino piperidin-1-yl) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (2- hydroxyethyl) -3- oxypiperazin -1- base) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (pyrrolidin-1-yl) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- (4- fluorine Phenyl) acetamide；
(R) -2- ((6- ((3S, 4R) -4- amino -3- fluorine resources -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (3- fluoro- 4- (methylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
Rel-2- ((6- (trans-) -4- amino -3- fluorine resources -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
(R) -2- ((6- ((3R, 4S) -4- amino -3- fluorine resources -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (the fluoro- 4- of 3- ((2- methoxy ethyl) amino) piperidin-1-yl) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (methyl (2- (pyrrolidin-1-yl) ethyl) amino) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -6- (3- ((dimethylamino) methyl) pyrrolidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((2- hydroxy-2-methyl propyl) amino) piperidin-1-yl) pyridine -2- base) Sulfenyl) -2- (4- fluorophenyl) acetamide；
(R) -2- ((6- ((3S, 4R) -4- amino -3- hydroxy piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((2- (diethylamino) ethyl) (methyl) amino) -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((2- ((R) -3- (dimethylamino) pyrrolidin-1-yl) ethyl) (methyl) amino) -4- second Yl pyridines -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((2- ((S) -3- (dimethylamino) pyrrolidin-1-yl) ethyl) (methyl) amino) -4- second Yl pyridines -2- base) sulfenyl) -2- phenyl-acetamides；
(R) -2- ((6- ((3R, 4R) -4- amino -3- fluorine resources -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
(R) -2- ((6- ((3S, 4S) -4- amino -3- fluorine resources -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (3- (methylamino) pyrrolidin-1-yl) pyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- (4- fluorophenyl) acetyl Amine；
(R) -2- ((6- ((3R, 4R) -4- amino -3- hydroxy piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((6- ((R) -3- amino-pyrrolidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((6- (3- (amino methyl) pyrrolidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- ethyl -6- (4- (methylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- (4- fluorobenzene Base) acetamide；
2- ((3,5- dicyano -6- (4- (cyclopropylamino) -3- fluorine resources -1- base) -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((6- ((S) -3- amino-pyrrolidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((6- ((2- ((R) -3- amino-pyrrolidine -1- base) ethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
3,5- dicyano -6- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- (4- Fluorophenyl) acetamide；
(S) -2- ((6- ((3S, 4R) -4- amino -3- fluorine resources -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (neopentyl amino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- (4- (three Methyl fluoride) phenyl) acetamide；
((3S, 4R) -1- (6- (((R) -2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) -3- hydroxy piperidine -4- base) t-butyl carbamate；
Rel- (cis-) -1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) -3- fluorine resources -4- base) t-butyl carbamate；
2- ((6- ((2- ((S) -3- amino-pyrrolidine -1- base) ethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((R) -3- (dimethylamino) pyrrolidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
((3R, 4S) -1- (6- (((R) -2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) -3- hydroxy piperidine -4- base) t-butyl carbamate；
Rel- (cis-) -1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) -3- fluorine resources -4- base) t-butyl carbamate；
2- ((3,5- dicyano -6- ((S) -3- (dimethylamino) pyrrolidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
(S) -2- ((6- ((3R, 4S) -4- amino -3- fluorine resources -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- ((2- hydroxy-2-methyl propyl) amino) pyrrolidin-1-yl) pyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
((3R, 4R) -1- (6- (((R) -2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) -3- hydroxy piperidine -4- base) t-butyl carbamate；
2- ((3,5- dicyano -6- ((S) -3- (dimethylamino) pyrrolidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- (4- fluorophenyl) acetamide；
Rel-2- ((cis- -4- amino -3- fluorine resources -1- base of 6-) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (methylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -6- (4- (dimethylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- ethyl -6- (4- (ethyl (methyl) amino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- (neopentyl amino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- ethyl -6- (4- (methyl (neopentyl) amino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -6- (4- (cyclopropylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- ethyl -6- (4- ((2- methoxy ethyl) amino) piperidin-1-yl) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- ((2,2- bis-fluoro ethyls) amino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((R) -2- ((neopentyl amino) methyl) morpholino) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -6- (2- ((dimethylamino) methyl) morpholino) -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -6- (2- ((diethylamino) methyl) morpholino) -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- (2- (pyrrolidin-1-yl methyl) morpholino) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
(R) -2- ((6- ((R) -2- (amino methyl) morpholino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((6- (2- (amino methyl) morpholino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (2- ((methylamino) methyl) morpholino) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((6- ((R) -2- (amino methyl) morpholino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -6- (3- ((dimethylamino) methyl) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (3- ((methylamino) methyl) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((S) -2- ((neopentyl amino) methyl) morpholino) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- ((neopentyl amino) methyl) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- amino-N- (((2S) -4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine-2- base) morpholine -2-yl) methyl)-2- methyl propanamide；
2- ((6- ((S) -3- (amino methyl) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -6- ((R) -2- ((diethylamino) methyl) morpholino) -4- ethylpyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- amino-N- (((2R) -4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine-2- base) morpholine -2-yl) methyl)-2- methyl propanamide；
2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- (3- fluorine pyridine -2- Base) acetamide；
2- ((6- ((S) -2- (amino methyl) morpholino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- amino-N- (((3S) -1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidines -3- base) methyl) -2- methyl propanamide；
2- amino-N- (((3S) -1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) piperidines -3- base) methyl) acetamide；
2- amino-N- (((2R) -4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine-2- base) morpholine -2-yl) methyl) acetamide；
2- ((6- ((R) -3- (amino methyl) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- (4- Fluorophenyl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((R) -3- ((neopentyl amino) methyl) piperidin-1-yl) pyridine -2- base) sulphur Base) -2- (4- fluorophenyl) acetamide；
2- amino-N- (((2S) -4- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine-2- base) morpholine -2-yl) methyl) acetamide；
N- (((R) -4- (6- (((R) -2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) morpholine -2-yl) methyl)-2- hydroxyl acetamide；
(S) -2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) Amino)-N- (2- hydroxyethyl)-N- methylacetamide；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- (methylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((6- (4- amino -4- methyl piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) Amino)-N- ((1- (hydroxymethyl) cyclopropyl) methyl)-N- methylacetamide；
2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine - 2- yl) azetidine -3- base) acetamide；
(2S) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl Pyridine -2- base) azetidine -3- base) -3- hydroxypropanamide；
2- ((6- ((S) -3- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((R) -3- hydroxyl pyrrolidine -1- base) -2- oxoethyl) (methyl) ammonia Base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
(2R) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl Pyridine -2- base) azetidine -3- base) -3- hydroxypropanamide；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) Amino)-N- (3- hydroxyl -2,2- dimethyl propyl)-N- methylacetamide；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((S) -3- hydroxyl pyrrolidine -1- base) -2- oxoethyl) (methyl) ammonia Base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((6- (4- amino -4- methyl piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((6- (4- (amino methyl) -4- fluorine resources -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide hydrochloride；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine -2- base) (first Base) amino)-N- (2- amino-ethyl) acetamide hydrochloride；
2- ((3,5- dicyano -4- ethyl -6- (methyl (2- oxo -2- (pyrrolidin-1-yl) ethyl) amino) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- (4- hydroxy piperidine -1- base) -2- oxoethyl) (methyl) amino) pyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (methyl (2- oxo -2- (piperazine -1- base) ethyl) amino) pyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (methyl (2- morpholino -2- oxoethyl) amino) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
(R) -2- ((6- ((S) -3- (amino methyl) -3- hydroxyl pyrrolidine -1- base) -3,5- dicyano -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- (guanidine radicals oxygroup) pyrrolidin-1-yl) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- amino-N- (2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) (methyl) amino) ethyl) -2- methyl propanamide；
2- ((6- ((2- (2- amino ethoxy) ethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
4- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) piperidin-4-yl) butyramide；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) Amino)-N- (2- amino-ethyl) acetamide；
2- ((6- ((2- (azetidine -1- base) -2- oxoethyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((6- ((R) -3- (amino methyl) -3- fluoropyrrolidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- (3- hydroxy azetidine -1- base) -2- oxoethyl) (methyl) ammonia Base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (guanidine radicals oxygroup) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((6- (3- aminoazetidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine；(single stereoisomers)
2- ((3,5- dicyano -4- ethyl -6- ((R) -3- (methylamino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- phenyl Acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((3R, 4S) -3- hydroxyl -4- (hydroxymethyl) pyrrolidin-1-yl) -2- oxygen For ethyl) (methyl) amino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
(R) -2- ((6- ((S) -3- (amino methyl) -3- fluoropyrrolidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine -2- base) (first Base) amino)-N- (1,3- dihydroxy propyl- 2- yl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- (oxetanes -3- base amino) piperidin-1-yl) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine -2- base) (first Base) amino)-N, N- bis- (2- hydroxyethyl) acetamide；
2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine - 2- yl) piperidin-4-yl) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (4- ((2- hydroxyethyl) amino) -4- methyl piperidine -1- base) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- (guanidine radicals oxygroup) ethyl) (methyl) amino) pyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((6- (4- ((2- amino-ethyl) amino) piperidin-1-yl) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- Phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((S) -2- (hydroxymethyl) morpholino) -2- oxoethyl) (methyl) ammonia Base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((2- ((cis-) -3,4- dihydroxy pyrrolidine -1- base) -2- oxoethyl) (methyl) ammonia Base) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((S) -3- (hydroxymethyl) pyrrolidin-1-yl) -2- oxoethyl) (first Base) amino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((3S, 4S) -3- hydroxyl -4- (hydroxymethyl) pyrrolidin-1-yl) -2- oxygen For ethyl) (methyl) amino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- (neopentyl amino) piperidin-1-yl) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((R) -3- (hydroxymethyl) pyrrolidin-1-yl) -2- oxoethyl) (first Base) amino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((2- ((3R, 4R) -3,4- dihydroxy pyrrolidine -1- base) -2- oxoethyl) (methyl) ammonia Base) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
(R) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl -3- (hydroxymethyl) pyrrolidin-1-yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
(2S) -2- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl Pyridine -2- base) piperidin-4-yl) propionamide；
2- ((6- (4- (2- amino ethoxy) piperidin-1-yl) -3,5- dicyano -4- cyclopropyl pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -4- cyclopropyl -6- (4- ((2- hydroxyethyl) amino) piperidin-1-yl) pyridine -2- base) sulfenyl) - 2- phenyl-acetamides；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) Amino)-N- (1,3- dihydroxy propyl- 2- yl) acetamide；
2- ((3,5- dicyano -6- ((2- ((3R, 5S) -3,5- dihydroxypiperdine -1- base) -2- oxoethyl) (methyl) ammonia Base) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((2- ((3S, 4S) -3,4- dihydroxy pyrrolidine -1- base) -2- oxoethyl) (methyl) ammonia Base) -4- ethylpyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- ((2- hydroxyethyl) amino) -4- (hydroxymethyl) piperidin-1-yl) pyridine - 2- yl) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((R) -2- (hydroxymethyl) morpholino) -2- oxoethyl) (methyl) ammonia Base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) Amino)-N- methoxyl acetamide；
2- ((3,5- dicyano -4- ethyl -6- ((2- ((3R, 4R) -3- hydroxyl -4- (hydroxymethyl) pyrrolidin-1-yl) -2- oxygen For ethyl) (methyl) amino) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) Amino)-N- (3- hydroxypropyl)-N- methylacetamide；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) Amino)-N- ((R) -2,3- dihydroxypropyl) acetamide；
2- ((6- (4- ((2- amino -2- oxoethyl) amino) piperidin-1-yl) -3,5- dicyano -4- cyclopropyl pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) Amino)-N, N- bis- (2- hydroxyethyl) acetamide；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) Amino)-N- (2- hydroxyethyl) acetamide；
2- ((6- ((3- aminopropyl) (methyl) amino) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((6- (3- (amino methyl) azetidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) Amino)-N- ((1- (hydroxymethyl) cyclopropyl) methyl) acetamide；
(R) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (2, 4- difluorophenyl) acetamide；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) Amino)-N- (3- (hydroxymethyl) oxetanes -3- base) acetamide；
2- ((3,5- dicyano -4- ethyl -6- (3- (guanidine radicals oxygroup) azetidine -1- base) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) Amino)-N- (3- hydroxypropyl) acetamide；
2- ((3,5- dicyano -6- (4- (2,3- dihydroxypropyl) -1,4- Diazesuberane -1- base) -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) Amino)-N- hydroxyl acetamide；
3- amino-N- (1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- cyclopropyl pyridine - 2- yl) azetidine -3- base) oxetanes -3- formamide；
2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (2- fluorobenzene Base) acetamide；
2- ((3,5- dicyano -6- ((S) -3- (cyclopropylamino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (methyl) Amino)-N- (3- hydroxyl -2,2- dimethyl propyl) acetamide；
N- (2- (4H-1,2,4- triazole-4-yl) ethyl) -2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3, 5- dicyano -4- ethylpyridine -2- base) (methyl) amino) acetamide；
N1- (2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) (first Base) amino) ethyl) oxamides；
2- ((6- (3- (amino methyl) -3- fluorine azetidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
(R) -2- ((3,5- dicyano -4- ethyl -6- ((R) -3- hydroxyl -3- (hydroxymethyl) pyrrolidin-1-yl) pyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- ((S) -3- ((2,2- bis-fluoro ethyls) amino) piperidin-1-yl) -4- ethylpyridine -2- base) sulphur Base) -2- phenyl-acetamides；
2- ((6- ((R) -3- amino piperidine -1- base) -3,5- dicyano -4- ethylpyridine -2- base) sulfenyl) -2- phenylacetyl Amine；
2- ((6- (4- amino piperidine -1- base) -3,5- dicyano -4-methoxypyridine -2- base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- ((S) -4- hydroxyl isoxazole alkane -2- base) pyridine -2- base) sulfenyl) -2- phenyl second Amide；
(R) -2- ((3,5- dicyano -4- ethyl -6- ((3- hydroxypropyl) (methyl) amino) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
2- ((3,5- dicyano -6- ((S) -3- hydroxyl pyrrolidine -1- base) -4-methoxypyridine -2- base) sulfenyl) -2- phenyl second Amide；
2- ((3,5- dicyano -4- ethyl -6- (4- (3- methoxyl group azetidine -1- base) piperidin-1-yl) pyridine -2- base) Sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -4- ethyl -6- (4- (3- methoxyl group azetidine -1- base) piperidin-1-yl) pyridine -2- base) Sulfenyl) -2- (4- fluorophenyl) acetamide；
(R) -2- ((3,5- dicyano -4- ethyl -6- ((2- hydroxyethyl) (methyl) amino) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
(R) -2- ((3,5- dicyano -4- ethyl -6- ((S) -3- hydroxyl pyrrolidine -1- base) pyridine -2- base) sulfenyl) -2- (4- Fluorophenyl) acetamide；
(R) -2- ((6- ((R) -3- (amino methyl) -3- hydroxyl pyrrolidine -1- base) -3,5- dicyano -4- ethylpyridine -2- Base) sulfenyl) -2- phenyl-acetamides；
2- ((3,5- dicyano -6- (4- (cyclobutyl (methyl) amino) piperidin-1-yl) -4- ethylpyridine -2- base) sulfenyl) -2- (4- fluorophenyl) acetamide；With
2- ((3,5- dicyano -4- ethyl -6- (methyl (1- methylpyrrolidin- 3- yl) amino) pyridine -2- base) sulfenyl) -2- benzene Yl acetamide；
Or its pharmaceutically acceptable salt or prodrug.
12. pharmaceutical composition, it includes the compound of any one of claim 7-11 or its pharmaceutically acceptable salts and medicine Acceptable excipient on.
13. the method that treatment is selected from following disease in the mammal for having this to need: syndrome, β hemoglobin before cancer, cancer Disease, drepanocytosis, sickle-cell anemia and beta Thalassemia comprising to the mammal dosage treatment effective amount Compound described in any one of claim 7-11 or its pharmaceutically acceptable salt.
14. method according to claim 13, wherein the mammal is behaved.
15. the method that treatment is selected from following disease in the mammal for having this to need: syndrome, β hemoglobin before cancer, cancer Disease, drepanocytosis, sickle-cell anemia and beta Thalassemia comprising to the mammal dosage treatment effective amount The compound of claim 11 or its pharmaceutically acceptable salt.
16. method according to claim 15, wherein the mammal is behaved.
17. method according to claim 14, wherein the cancer is selected from: the cancer of the brain (glioma), glioblastoma, star are thin Born of the same parents' tumor, glioblastoma multiforme, Bannayan-Zonana syndrome, cowden's disease, Lhermitte-Duclos disease, mammary gland Cancer, colon cancer, head and neck cancer, kidney, lung cancer, liver cancer, melanoma, oophoroma, cancer of pancreas, gland cancer, duct adenocarcinoma, gland carcinoma squamosum, Acinar cell carcinoma, glucagonoma of pancreas, insulinoma, prostate cancer, sarcoma and thyroid cancer.
18. method according to claim 16, in which: the cancer is thin selected from the cancer of the brain (glioma), glioblastoma, star Born of the same parents' tumor, glioblastoma multiforme, Bannayan-Zonana syndrome, cowden's disease, Lhermitte-Duclos disease, mammary gland Cancer, colon cancer, head and neck cancer, kidney, lung cancer, liver cancer, melanoma, oophoroma, cancer of pancreas, gland cancer, duct adenocarcinoma, gland carcinoma squamosum, Acinar cell carcinoma, glucagonoma of pancreas, insulinoma, prostate cancer, sarcoma and thyroid cancer.
19. compound according to any one of claims 7-11 or its pharmaceutically acceptable salt are in preparation for treating Or the purposes in the drug of mitigation cancer seriousness.
20. inhibiting the active method of DNMT1 in the mammal for thering is this to need comprising have to the mammal drug treatment The described in any item compounds or its pharmaceutically acceptable salt as claim in claims 7-11 of effect amount.
21. method according to claim 20, wherein the mammal is behaved.
22. the method for the treatment of cancer in the mammal for thering is this to need comprising: to the mammal dosage treatment effective amount Described in any item compounds or its pharmaceutically acceptable salt a) as claim in claims 7-11；With
B) at least one antitumor agent.
23. method according to claim 22, wherein at least one antitumor agent is selected from: anti-micro-pipe agent, platinum ligand complex Object, alkylating agent, antibiotic formulations, Topoisomerase II inhibitors, antimetabolite, topoisomerase I inhibitor, hormone and hormone Analog, signal transduction pathway inhibitor, nonreceptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agent, promote apoptosis agent, Cell cycle signals inhibitor, protease inhibitors, cancer metabolic poison, anti-PD-L1 agent, PD-1 antagonist, immunological regulation Agent, STING modulating compound, CD39 inhibitor, A2a and A2a adenosine antagonist, TLR4 antagonist, ICOS antibody and OX40 are anti- Body.
24. pharmaceutical composition, it includes:
A) described in any item compounds or its pharmaceutically acceptable salt as claim in claims 7-11；With
B) at least one antitumor agent.
25. pharmaceutical composition as claimed in claim 24, is used for treating cancer.
26. method according to claim 13, wherein the cancer is selected from: breast cancer, inflammatory breast cancer, duct carcinoma, lobular carcinoma, Colon cancer, cancer of pancreas, insulinoma, gland cancer, duct adenocarcinoma, gland carcinoma squamosum, acinar cell carcinoma, glucagonoma of pancreas, cutaneum carcinoma, Melanoma, metastatic melanoma, lung cancer, Small Cell Lung Cancer, non-small cell lung cancer, squamous cell carcinoma, gland cancer, large cell carcinoma, brain Cancer (glioma), glioblastoma, astrocytoma, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden's disease, Lhermitte-Duclos disease, Wilm'stumor, Ewing's sarcoma, rhabdomyosarcoma, ependymoma, pith mother cells Tumor, head and neck cancer, kidney, liver cancer, melanoma, oophoroma, cancer of pancreas, gland cancer, duct adenocarcinoma, gland carcinoma squamosum, acinar cell carcinoma, pancreas Glucagonoma, insulinoma, prostate cancer, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid cancer, lymphatic T cell Leukaemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy cell leukemia, acute lymphoblastic leukemia, Acute myeloid leukaemia, chronic neutrophilic leukocytic leukemia, acute lymphocytic T cell leukaemia, plasmacytoma, at exempting from Epidemic disease cell mast cell leukemia, jacket cell leukaemia, Huppert's disease, megakaryoblast leukaemia, Huppert's disease, Acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, Hodgkin lymphoma, Fei Huoqi Golden lymthoma, lymphoblastic t cell lymphoma, Burkitt lymphoma, follicular lymphoma, neuroblastoma, bladder Cancer, urothelium cancer, carcinoma of vulva, cervical carcinoma, carcinoma of endometrium, kidney, celiothelioma, cancer of the esophagus, salivary-gland carcinoma, liver cell Cancer, gastric cancer, nasopharyngeal carcinoma, carcinoma of mouth, mouth cancer, GIST (gastrointestinal stromal tumor), neuroendocrine carcinoma and carcinoma of testis.
27. method according to claim 26, wherein the mammal is behaved.
28. preparation comprising pharmaceutically acceptable excipient and described in any item formulas as claim in claims 7-11 (IVbbr), (Vbbr), the method for the pharmaceutical composition of (VIbbr) or (Qb) compound or its pharmaceutically acceptable salt, this method includes will Formula (IVbbr), (Vbbr), (VIbbr) or (Qb) compound or its pharmaceutically acceptable salt and pharmaceutically acceptable figuration Agent combination.
29. method according to claim 14, wherein syndrome is selected from before the cancer: cervical intraepithelial neoplasia (CIN), meaning are not Bright monoclonal gamma globulin (MGUS), myelodysplastic syndrome, alpastic anemia, cervical lesions, cutaneous nevus Tumour (PIN), in situ ductal carcinoma (DCIS), polyp of colon and heavy type hepatitis (in conduit) in (preceding melanoma), prostatic epithelium Or cirrhosis.
30. pharmaceutical composition, it includes:
A) described in any item compounds or its pharmaceutically acceptable salt as claim in claims 7-11；With
B) at least one for treating the medicament of β hemoglobinopathy.
31. pharmaceutical composition as claimed in claim 30 is used to treat drepanocytosis.
32. pharmaceutical composition as claimed in claim 30 is used to treat sickle-cell anemia.
33. pharmaceutical composition as claimed in claim 30 is used to treat beta Thalassemia.
34. the method as described in claim 1, wherein the compound is selected from:
Biphosphate 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) Pyrrolidin-3-yl ester；
Biphosphate 1- (6- ((2- amino -1- (4- fluorophenyl) -2- oxoethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) pyrrolidin-3-yl ester；
Biphosphate 2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) (methyl) amino) ethyl ester；
Biphosphate 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) Azetidine -3- base ester；
(2S) -2- amino -3 Methylbutanoic acid 2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyan Base -4- ethylpyridine -2- base) piperidin-4-yl) oxygroup) ethyl ester；
Biphosphate 2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) piperidin-4-yl) oxygroup) ethyl ester；With
Biphosphate 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) Piperidin-4-yl ester；
Or its pharmaceutically acceptable salt.
35. the prodrug of compound as claimed in claim 11, the compound is selected from:
Biphosphate 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) Pyrrolidin-3-yl ester；
Biphosphate 1- (6- ((2- amino -1- (4- fluorophenyl) -2- oxoethyl) sulfenyl) -3,5- dicyano -4- ethyl pyrrole Pyridine -2- base) pyrrolidin-3-yl ester；
Biphosphate 2- ((6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- Base) (methyl) amino) ethyl ester；
Biphosphate 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) Azetidine -3- base ester；
(2S) -2- amino -3 Methylbutanoic acid 2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyan Base -4- ethylpyridine -2- base) piperidin-4-yl) oxygroup) ethyl ester；
Biphosphate 2- ((1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine - 2- yl) piperidin-4-yl) oxygroup) ethyl ester；With
Biphosphate 1- (6- ((2- amino -2- oxo -1- phenylethyl) sulfenyl) -3,5- dicyano -4- ethylpyridine -2- base) Piperidin-4-yl ester；
Or its pharmaceutically acceptable salt.
36. the method as described in claim 1, wherein the compound are as follows: 2- ((3,5- dicyano -4- (furans -2- base) -6- (4- methyl-1,4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
Or its pharmaceutically acceptable salt or prodrug.
37. compound as claimed in claim 7, are as follows: 2- ((3,5- dicyano -4- (furans -2- base) -6- (4- methyl-1, 4- Diazesuberane -1- base) pyridine -2- base) sulfenyl) -2- phenyl-acetamides；
Or its pharmaceutically acceptable salt or prodrug.
38. the method that treatment is selected from following disease in the mammal for having this to need: nephrosis, diabetes, foot are thin Cellular damage, atherosclerosis, psoriasis, idiopathic pulmonary fibrosis, chorionitis, cirrhosis, rheumatoid arthritis and A Er Ci Haimo disease comprising to described in any item compounds as claim in claims 7-11 of the mammal dosage treatment effective amount Or its pharmaceutically acceptable salt.
39. method as claimed in claim 38, wherein the mammal is behaved.
40. pharmaceutical composition, it includes 0.5 to 1,000mg compound as defined in any one of claim 1,2 or 6 or Its pharmaceutically acceptable salt and 0.5 to 1,000mg pharmaceutically acceptable excipient.
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